Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, and preparation and use thereof

ABSTRACT

The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nACh receptors), activation of nACh receptors, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds (e.g., indazoles and benzothiazoles), which act as ligands for the α7 nACh receptor subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.

This application is a continuation of Ser. No. 12/631,435, filed Dec. 4,2009, which is a continuation of application Ser. No. 11/089,533, filedMar. 25, 2005, now abandoned, and this application claims the benefit ofU.S. Provisional application Ser. No. 60/555,951, filed Mar. 25, 2004,and U.S. Provisional application Ser. No. 60/616,033, filed Oct. 6,2004, the entire disclosures of which are hereby incorporated byreference.

This application is also related to U.S. patent application Ser. No.10/669,645, filed Sep. 25, 2003, which claims the benefit of U.S.Provisional application Ser. No. 60/413,151, filed Sep. 25, 2002, andU.S. Provisional application Ser. No. 60/448,469, filed Feb. 21, 2003,the entire disclosures of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates generally to the field of ligands fornicotinic acetylcholine receptors (nAChR), activation of nAChRs, and thetreatment of disease conditions associated with defective ormalfunctioning nicotinic acetylcholine receptors, especially of thebrain. Further, this invention relates to novel compounds, which act asligands for the α7 nAChR subtype, methods of preparing such compounds,compositions comprising such compounds, and methods of use thereof.

BACKGROUND OF THE INVENTION

There are two types of receptors for the neurotransmitter,acetylcholine: muscarinic receptors and nicotinic receptors, based onthe selectivity of action of muscarine and nicotine, respectively.Muscarinic receptors are G-protein coupled receptors. Nicotinicreceptors are members of the ligand-gated ion channel family. Whenactivated, the conductance of ions across the nicotinic ion channelsincreases.

Nicotinic alpha-7 receptor protein forms a homo-pentameric channel invitro that is highly permeable to a variety of cations (e.g., Ca⁺⁺).Each nicotinic alpha-7 receptor has four transmembrane domains, namedM1, M2, M3, and M4. The M2 domain has been suggested to form the walllining the channel. Sequence alignment shows that nicotinic alpha-7 ishighly conserved during evolution. The M2 domain that lines the channelis identical in protein sequence from chicken to human. For discussionsof the alpha-7 receptor, see, e.g., Revah et al. (1991), Nature, 353,846-849; Galzi et al. (1992), Nature 359, 500-505; Fucile et al. (2000),PNAS 97(7), 3643-3648; Briggs et al. (1999), Eur. J. Pharmacol. 366(2-3), 301-308; and Gopalakrishnan et al. (1995), Eur. J. Pharmacol.290(3), 237-246.

The nicotinic alpha-7 receptor channel is expressed in various brainregions and is believed to be involved in many important biologicalprocesses in the central nervous system (CNS), including learning andmemory. Nicotinic alpha-7 receptors are localized on both presynapticand postsynaptic terminals and have been suggested to be involved inmodulating synaptic transmission. It is therefore of interest to developnovel compounds, which act as ligands for the α7nACh receptor subtype,for the treatment of disease conditions associated with defective ormalfunctioning nicotinic acetylcholine receptors.

SUMMARY OF THE INVENTION

This invention relates to novel compounds, which act as ligands for theα7 nACh receptor subtype, methods of preparing such compounds,compositions comprising such compounds, and methods of use thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes compounds of Formulas I, II, III, or IV:

wherein

-   -   A is

-   -   X is O or S;    -   R′ is H, alkyl having 1 to 4 carbon atoms, halogenated alkyl        having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon        atoms, or cycloalkylalkyl having 4 to 7 carbon atoms;    -   R is H, F, Cl, Br, I, OH, CN, COH, NR⁶R⁷, carboxy, CONR⁶R⁷,        NR²COR⁸, NR²COOR⁸, NR²CSR⁸, NR²CONR²R⁹, NR²CSNR²R⁹, NR²SO₂R¹⁰,        NR²CONR⁶R⁷, NR²CSNR⁶R⁷, NR²R⁹, SO₂R¹⁰, SOR¹⁰,        —O—(C₁₋₆-alkyl-O)₁₋₂—C₁₋₆-alkyl, NR²—C₁₋₆-alkyl-NR⁶R⁷,        NR²—C₁₋₆-alkyl-CONR⁶R⁷, NR²—CO—C₁₋₆-alkyl-Ar,        NR²—C₁₋₆-alkyl-CO—O—R², NR²—C₁₋₆-alkyl-NR²(CO—O—R²),        —C₁₋₆-alkyl-NR², —O—C₁₋₆-alkyl-NR⁶R⁷, alkyl having 1 to 4 carbon        atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF₃),        alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon        atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl,        fluorinated alkyl, alkenyl, or alkynyl groups are in each        unsubstituted or substituted by Ar or Het (e.g., phenylacetylene        C₆H₅—C≡C—), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl        having 5 to 8 carbon atoms which is unsubstituted or substituted        by HCO—, C₁₋₆-alkoxy, NR⁶R⁷, CO—NR⁶R⁷, C₂₋₆-alkoxycarbonyl, or        —CO—R¹⁰, cycloalkylalkyl having 4 to 7 carbon atoms,        cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to        4 carbon atoms (e.g., OCH₃), cycloalkoxy having 3 to 7 carbon        atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,        cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (e.g.,        SCH₃), fluorinated alkoxy having 1 to 4 carbon atoms (e.g.,        OCF₃, OCHF₂), hydroxyalkyl having 1 to 4 carbon atoms,        fluorinated hydroxyalkyl having 1 to 4 carbon atoms (e.g.,        2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl),        hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated        hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having        1 to 4 carbon atoms, dialkylamino wherein each alkyl group        independently has 1 to 4 carbon atoms, alkoxycarbonyl having 2        to 6 carbon atoms, Ar, Het, OAr, OHet, Carbo-O,        Ar—C₁₋₆-alkyl-O—, Het-C₁₋₆-alkyl-O—, Het-CO-Het-,        Het-C₁₋₆-alkyl-NR²—, or Ar—C₁₋₆-alkyl-Het-O—,        -   with the proviso that R is not NH₂; or    -   R is of one of the following formulas

-   -   n is 2 to 4;    -   m is 3 to 5; or    -   two R can together form a 5-membered fused ring structure        containing at least one N atom;    -   R¹ is H, F, Cl, Br, I, OH, CN, nitro, NH₂, COH, NR⁶R⁷, carboxy,        CONR⁶R⁷, NR²COR⁸, NR²COOR⁸, NR²CSR⁸, NR²CONR²R⁹, NR²CSNR²R⁹,        NR²SO₂R¹⁰, NR²CONR⁶R⁷, NR²CSNR⁶R⁷, NR²R⁹, SO₂R¹⁰, SOR¹⁰,        —O—(C₁₋₆-alkyl-O)₁₋₂—C₁₋₆-alkyl, NR²—C₁₋₆-alkyl-NR⁶R⁷,        NR²—C₁₋₆-alkyl-CONR⁶R⁷, NR²—CO—C₁₋₆-alkyl-Ar,        NR²—C₁₋₆-alkyl-CO—O—R², NR²—C₁₋₆-alkyl-NR²(CO—O—R²),        —C₁₋₆-alkyl-NR², —O—C₁₋₆-alkyl-NR⁶R⁷, alkyl having 1 to 4 carbon        atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF₃),        alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon        atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl,        fluorinated alkyl, alkenyl, or alkynyl groups are in each        unsubstituted or substituted by Ar or Het (e.g., phenylacetylene        C₆H₅—C≡C—), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl        having 5 to 8 carbon atoms which is unsubstituted or substituted        by HCO—, C₁₋₆-alkoxy, NR⁶R⁷, CO—NR⁶R⁷, C₂₋₆-alkoxycarbonyl, or        —CO—R¹⁰, cycloalkylalkyl having 4 to 7 carbon atoms,        cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to        4 carbon atoms (e.g., OCH₃), cycloalkoxy having 3 to 7 carbon        atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,        cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (e.g.,        SCH₃), fluorinated alkoxy having 1 to 4 carbon atoms (e.g.,        OCF₃, OCHF₂), hydroxyalkyl having 1 to 4 carbon atoms,        fluorinated hydroxyalkyl having 1 to 4 carbon atoms (e.g.,        2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl),        hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated        hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having        1 to 4 carbon atoms, dialkylamino wherein each alkyl group        independently has 1 to 4 carbon atoms, alkoxycarbonyl having 2        to 6 carbon atoms, Ar, Het, OAr, OHet, Carbo-O,        Ar—C₁₋₆-alkyl-O—, Het-C₁₋₆-alkyl-O—, Het-CO-Het-,        Het-C₁₋₆-alkyl-NR²—, or Ar—C₁₋₆-alkyl-Het-O—; or    -   R¹ is of one of the following formulas

or

-   -   two R¹ can together form a 5-membered fused ring structure        containing at least one N atom;    -   R² is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl        having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon        atoms, cycloalkylalkyl having 4 to 7 carbon atoms, fluorinated        C₁₋₄-alkyl-CO—, C₃₋₇-cycloalkyl-CO—, C₁₋₄-alkyl-NH—CO—,        C₃₋₇-cycloalkyl-NH—CO—, Het, Ar—C₁₋₄-alkyl-, Ar—C₁₋₄-alkyl-CO—,        Ar—C₁₋₄-alkyl-SO₂—, C₁₋₄-alkyl-O—C₁₋₄-alkyl- (e.g.,        CH₂CH₂—O—CH₃), or Ar—C₁₋₄-alkyl-NH—CO—;    -   R³ is H, F, Cl, Br, I, OH, CN, nitro, NH₂, COH, NR⁶R⁷, carboxy,        CONR⁶R⁷, NR²COR⁸, NR²COOR⁸, NR²CSR⁸, NR²CONR²R⁹, NR²CSNR²R⁹,        NR²SO₂R¹⁰, NR²CONR⁶R⁷, NR²CSNR⁶R⁷, NR²R⁹, SO₂R¹⁰, SOR¹⁰,        —O—(C₁₋₆-alkyl-O)₁₋₂—C₁₋₆-alkyl, NR²—C₁₋₆-alkyl-NR⁶R⁷,        NR²—C₁₋₆-alkyl-CONR⁶R⁷, NR²—CO—C₁₋₆-alkyl-Ar,        NR²—C₁₋₆-alkyl-CO—O—R², NR²—C₁₋₆-alkyl-NR²(CO—O—R²),        —C₁₋₆-alkyl-NR², —O—C₁₋₆-alkyl-NR⁶R⁷, alkyl having 1 to 4 carbon        atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF₃),        alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon        atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl,        fluorinated alkyl, alkenyl, or alkynyl groups are in each        unsubstituted or substituted by Ar or Het (e.g., phenylacetylene        C₆H₅—C≡C—), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl        having 5 to 8 carbon atoms which is unsubstituted or substituted        by HCO—, C₁₋₆-alkoxy, NR⁶R⁷, CO—NR⁶R⁷, C₂₋₆-alkoxycarbonyl, or        —CO—R¹⁰, cycloalkylalkyl having 4 to 7 carbon atoms,        cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to        4 carbon atoms (e.g., OCH₃), cycloalkoxy having 3 to 7 carbon        atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,        cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (e.g.,        SCH₃), fluorinated alkoxy having 1 to 4 carbon atoms (e.g.,        OCF₃, OCHF₂), hydroxyalkyl having 1 to 4 carbon atoms,        fluorinated hydroxyalkyl having 1 to 4 carbon atoms (e.g.,        2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl),        hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated        hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having        1 to 4 carbon atoms, dialkylamino wherein each alkyl group        independently has 1 to 4 carbon atoms, alkoxycarbonyl having 2        to 6 carbon atoms, Ar, Het, OAr, OHet, Carbo-O,        Ar—C₁₋₆-alkyl-O—, Het-C₁₋₆-alkyl-O—, Het-CO-Het-,        Het-C₁₋₆-alkyl-NR²—, or Ar—C₁₋₆-alkyl-Het-O—; or    -   R³ is of one of the following formulas

or

-   -   two R³ can together form a 5-membered fused ring structure        containing at least one N atom;    -   R⁴ is H, F, Cl, Br, I, OH, CN, nitro, NH₂, COH, NR⁶R⁷, carboxy,        CONR⁶R⁷, NR²COR⁸, NR²COOR⁸, NR²CSR⁸, NR²CONR²R⁹, NR²CSNR²R⁹,        NR²SO₂R¹⁰, NR²CONR⁶R⁷, NR²CSNR⁶R⁷, NR²R⁹, SO₂R¹⁰, SOR¹⁰,        —O—(C₁₋₆-alkyl-O)₁₋₂—C₁₋₆-alkyl, NR²—C₁₋₆-alkyl-NR⁶R⁷,        NR²—C₁₋₆-alkyl-CONR⁶R⁷, NR²—CO—C₁₋₆-alkyl-Ar,        NR²—C₁₋₆-alkyl-CO—O—R², NR²—C₁₋₆-alkyl-NR²(CO—O—R²),        —C₁₋₆-alkyl-NR², —O—C₁₋₆-alkyl-NR⁶R⁷, alkyl having 1 to 4 carbon        atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF₃),        alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon        atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl,        fluorinated alkyl, alkenyl, or alkynyl groups are in each        unsubstituted or substituted by Ar or Het (e.g., phenylacetylene        C₆H₅—C≡C—), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl        having 5 to 8 carbon atoms which is unsubstituted or substituted        by HCO—, C₁₋₆-alkoxy, NR⁶R⁷, CO—NR⁶R⁷, C₂₋₆-alkoxycarbonyl, or        —CO—R¹⁰, cycloalkylalkyl having 4 to 7 carbon atoms,        cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to        4 carbon atoms (e.g., OCH₃), cycloalkoxy having 3 to 7 carbon        atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,        cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (e.g.,        SCH₃), fluorinated alkoxy having 1 to 4 carbon atoms (e.g.,        OCF₃, OCHF₂), hydroxyalkyl having 1 to 4 carbon atoms,        fluorinated hydroxyalkyl having 1 to 4 carbon atoms (e.g.,        2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl),        hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated        hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having        1 to 4 carbon atoms, dialkylamino wherein each alkyl group        independently has 1 to 4 carbon atoms, alkoxycarbonyl having 2        to 6 carbon atoms, Ar, Het, OAr, OHet, Carbo-O,        Ar—C₁₋₆-alkyl-O—, Het-C₁₋₆-alkyl-O—, Het-CO-Het-,        Het-C₁₋₆-alkyl-NR²—, or Ar—C₁₋₆-alkyl-Het-O—; or    -   R⁴ is of one of the following formulas

or

-   -   two R⁴ can together form a 5-membered fused ring structure        containing at least one N atom;    -   R⁵ is H, F, Cl, Br, I, OH, CN, nitro, NH₂, carboxy, CONR⁶R⁷,        NR²COR⁸, NR²CSR⁸, NR²CONR²R⁹, NR²CSNR²R⁹, NR²SO₂R¹⁰, NR²CONR⁶R⁷,        NR²CSNR⁶R⁷, NR²R⁹, SO₂R¹⁰, SOR¹⁰, alkyl having 1 to 4 carbon        atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF₃),        alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon        atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl,        fluorinated alkyl, alkenyl, or alkynyl groups are in each        unsubstituted or substituted by Ar or Het (e.g., phenylacetylene        C₆H₅—C≡C—), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl        having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon        atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy        having 1 to 4 carbon atoms (e.g., OCH₃), cycloalkoxy having 3 to        7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms        (e.g., cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms        (e.g., SCH₃), fluorinated alkoxy having 1 to 4 carbon atoms        (e.g., OCF₃, OCHF₂), hydroxyalkyl having 1 to 4 carbon atoms,        fluorinated hydroxyalkyl having 1 to 4 carbon atoms (e.g.,        2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl),        hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated        hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having        1 to 4 carbon atoms, dialkylamino wherein each alkyl group        independently has 1 to 4 carbon atoms, alkoxycarbonyl having 2        to 6 carbon atoms, Ar, Het, OAr, or OHet;    -   R⁶ and R⁷ are each, independently, H, alkyl having 1 to 4 carbon        atoms, alkoxyalkyl having 2 to 8 carbon atoms, cycloalkyl having        3 to 7 carbon atoms, or cycloalkylalkyl having 4 to 7 carbon        atoms, or R⁶ and R⁷ together are an alkylene group containing        4-6 carbon atoms which forms a ring with the N atom (e.g.,        piperidinyl, pyrrolidinyl);    -   R⁸ is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl        having 1 to 4 carbon atoms (e.g., CF₃), alkenyl having 3 to 6        carbon atoms, alkynyl having 3 to 6 carbon atoms (e.g.,        propynyl, pentenyl), wherein the alkyl, fluorinated alkyl,        alkenyl, or alkynyl groups are in each unsubstituted or        substituted by Ar or Het (e.g., phenylacetylene C₆H₅—C≡C—),        cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to        8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms,        cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl        having 1 to 4 carbon atoms, fluorinated hydroxyalkyl having 1 to        4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms,        dialkylamino wherein each alkyl group independently has 1 to 4        carbon atoms, Ar, or Het;    -   R⁹ is Ar, Ar-alkyl wherein the alkyl portion has 1 to 4 carbon        atoms, or Het;    -   R¹⁰ is alkyl having 1 to 4 carbon atoms, fluorinated alkyl        having 1 to 4 carbon atoms (e.g., CF₃), alkenyl having 3 to 6        carbon atoms, alkynyl having 3 to 6 carbon atoms (e.g.,        propynyl, pentenyl), wherein the alkyl, fluorinated alkyl,        alkenyl, or alkynyl groups are in each unsubstituted or        substituted by Ar or Het (e.g., phenylacetylene C₆H₅—C≡C—),        cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to        8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms,        cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl        having 2 to 4 carbon atoms, fluorinated hydroxyalkyl having 2 to        4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms,        dialkylamino wherein each alkyl group independently has 1 to 4        carbon atoms, NR⁶R⁷, NR²R⁸, Ar, or Het;    -   Ar is an aryl group containing 6 to 10 carbon atoms which is        unsubstituted or substituted one or more times by alkyl having 1        to 8 C atoms, alkoxy having 1 to 8 C atoms, halogen (F, Cl, Br,        or I, preferably F or Cl), dialkylamino wherein the alkyl        portions each have 1 to 8 C atoms, amino, cyano, hydroxyl,        nitro, halogenated alkyl having 1 to 8 C atoms, halogenated        alkoxy having 1 to 8 C atoms, hydroxyalkyl having 1 to 8 C        atoms, hydroxyalkoxy having 2 to 8 C atoms, alkenyloxy having 3        to 8 C atoms, alkylthio having 1 to 8 C atoms, alkylsulphinyl        having 1 to 8 C atoms, alkylsulphonyl having 1 to 8 C atoms,        monoalkylamino having 1 to 8 C atoms, cycloalkylamino wherein        the cycloalkyl group has 3 to 7 C atoms and is optionally        substituted, aryloxy wherein the aryl portion contains 6 to 10        carbon atoms (e.g., phenyl, naphthyl, biphenyl) and is        optionally substituted, arylthio wherein the aryl portion        contains 6 to 10 carbon atoms (e.g., phenyl, naphthyl, biphenyl)        and is optionally substituted, cycloalkyloxy wherein the        cycloalkyl group has 3 to 7 C atoms and is optionally        substituted, sulfo, sulfonylamino, acylamido (e.g., acetamido),        acyloxy (e.g., acetoxy) or combinations thereof;    -   Het is a heterocyclic group, which is fully saturated, partially        saturated or fully unsaturated, having 5 to 10 ring atoms in        which at least 1 ring atom is a N, O or S atom, which is        unsubstituted or substituted one or more times by halogen (F,        Cl, Br, or I, preferably F or Cl), aryl having 6 to 10 carbon        atoms (e.g., phenyl, naphthyl, biphenyl) which is optionally        substituted, alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C        atoms, cycloalkyl having 3 to 7 carbon atoms, cyano,        trifluoromethyl, nitro, oxo, OH, alkoxycarbonylalkyl having 3 to        8 carbon atoms, amino, monoalkylamino having 1 to 8 C atoms,        dialkylamino wherein each alkyl group has 1 to 8 C atoms,        SO₂R¹¹, —CXR¹¹, piperidinylethyl or combinations thereof;    -   Carbo is a partially unsaturated carbocyclic group having 5 to        14 carbon atoms, which is unsubstituted or substituted one or        more times by halogen, alkyl having 1 to 8 C atoms, alkoxy        having 1 to 8 C atoms, hydroxy, nitro, cyano, oxo, or        combinations thereof (e.g., indanyl, tetrahydronaphthenyl,        etc.); and    -   R¹¹ is alkyl having 1 to 4 carbon atoms, halogenated alkyl        having 1 to 4 carbon atoms (e.g., CF₃), alkenyl having 3 to 6        carbon atoms, alkynyl having 3 to 6 carbon atoms (e.g.,        propynyl, pentenyl), wherein the alkyl, halogenated alkyl,        alkenyl, or alkynyl groups are in each unsubstituted or        substituted by Ar or Het (e.g., phenylacetylene C₆H₅—C≡C—),        cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to        8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms,        cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl        having 2 to 4 carbon atoms, fluorinated hydroxyalkyl having 2 to        4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms,        dialkylamino wherein each alkyl group independently has 1 to 4        carbon atoms, or Ar; and    -   wherein said compound is optionally in the form of an N-oxide

In Formula I, when A is an indazolyl group of subformula (a), it ispreferably attached to the remainder of the compound via its 3, 4 or 7position, particularly via the 3-position. When A is a benzothiazolylgroup of subformula (b), it is preferably attached to the remainder ofthe compound via its 4 or 7 position. When A is a benzoisothiazolylgroup of subformula (c), it is preferably attached to the remainder ofthe compound via its 3, 4 or 7 position, particularly via the3-position. When A is a benzisoxazolyl group of subformula (d), it ispreferably attached to the remainder of the compound via its 3, 4 or 7position, particularly via the 3-position.

Similarly, in Formula II, when A is an indazolyl group of subformula(a), it is preferably attached to the remainder of the compound via its3, 4 or 7 position, particularly via the 3-position. When A is abenzothiazolyl group of subformula (b), it is preferably attached to theremainder of the compound via its 4 or 7 position. When A is abenzoisothiazolyl group of subformula (c), it is preferably attached tothe remainder of the compound via its 3, 4 or 7 position, particularlyvia the 3-position. When A is a benzisoxazolyl group of subformula (d),it is preferably attached to the remainder of the compound via its 3, 4or 7 position, particularly via the 3-position.

Also, in Formula III, when A is an indazolyl group of subformula (a), itis preferably attached to the remainder of the compound via its 3, 4 or7 position, particularly via the 3-position. When A is a benzothiazolylgroup of subformula (b), it is preferably attached to the remainder ofthe compound via its 4 or 7 position. When A is a benzoisothiazolylgroup of subformula (c), it is preferably attached to the remainder ofthe compound via its 3, 4 or 7 position, particularly via the3-position. When A is a benzisoxazolyl group of subformula (d), it ispreferably attached to the remainder of the compound via its 3, 4 or 7position, particularly via the 3-position.

Further, in Formula IV, when A is an indazolyl group of subformula (a),it is preferably attached to the remainder of the compound via its 3, 4or 7 position, particularly via the 3-position. When A is abenzothiazolyl group of subformula (b), it is preferably attached to theremainder of the compound via its 4 or 7 position. When A is abenzoisothiazolyl group of subformula (c), it is preferably attached tothe remainder of the compound via its 3, 4 or 7 position, particularlyvia the 3-position. When A is a benzisoxazolyl group of subformula (d),it is preferably attached to the remainder of the compound via its 3, 4or 7 position, particularly via the 3-position.

In Formulas I-IV, the indazolyl, benzothiazolyl, benzoisothiazolyl, andbenzisoxazolyl groups of A can be attached to the remainder of thestructure via any suitable attachment point. The following subformulasillustrate some of the preferred attachments between the indazole,benzothiazole, benzoisothiazole, and benzisoxazole groups and theremainder of the structure.

The following subformulas further illustrate some of the preferredattachments between the indazolyl, benzothiazolyl, benzoisothiazolyl andbenzisoxazolyl groups and the remainder of the structure.

The following subformulas further illustrate some of the preferredattachments between the indazolyl, benzothiazolyl, benzoisothiazolyl andbenzisoxazolyl groups and the remainder of the structure.

The following subformulas further illustrate some of the preferredattachments between the indazolyl, benzothiazolyl, benzoisothiazolyl andbenzisoxazolyl groups and the remainder of the structure.

X is preferably O.

R′ is preferably H or CH₃, particularly H.

Alkyl throughout means a straight-chain or branched-chain aliphatichydrocarbon radical having preferably 1 to 4 carbon atoms. Suitablealkyl groups include but are not limited to methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, and tert-butyl.

Alkenyl throughout means a straight-chain or branched-chain aliphatichydrocarbon radical having preferably 2 to 6 carbon atoms. Suitablealkenyl groups include but are not limited to ethenyl, propenyl,butenyl, and pentenyl.

Alkynyl throughout means a straight-chain or branched-chain aliphatichydrocarbon radical having preferably 2 to 6 carbon atoms. Suitablealkynyl groups include but are not limited to ethyne, propyne, butyne,etc.

Alkoxy means alkyl-O— groups in which the alkyl portion preferably has 1to 4 carbon atoms. Suitable alkoxy groups include but are not limited tomethoxy, ethoxy, propoxy, isopropoxy, isobutoxy, and sec-butoxy.

Alkylthio means alkyl-S— groups in which the alkyl portion preferablyhas 1 to 4 carbon atoms. Suitable alkylthio groups include but are notlimited to methylthio and ethylthio.

Cycloalkyl means a cyclic, bicyclic or tricyclic saturated hydrocarbonradical having 3 to 7 carbon atoms. Suitable cycloalkyl groups includebut are not limited to cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl. Other suitable cycloalkyl groups include but are not limitedto spiropentyl, bicyclo[2.1.0]pentyl, and bicyclo[3.1.0]hexyl.

Cycloalkoxy means cycloalkyl-O— groups in which the cycloalkyl portionpreferably is a cyclic, bicyclic or tricyclic saturated hydrocarbonradical having 3 to 7 carbon atoms.

Cycloalkylalkyl groups contain 4 to 7 carbon atoms. Suitablecycloalkylalkyl groups include but are not limited to, for example,cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, andcyclopentylmethyl.

Cycloalkylalkoxy groups contain 4 to 7 carbon atoms. Suitablecycloalkylalkoxy groups include but are not limited to, for example,cyclo-propylmethyloxy, cyclopropylethyloxy, cyclobutylmethyloxy, andcyclo-pentylmethyloxy.

The cycloalkyl and cycloalkylalkyl groups can be substituted byC₁₋₄-alkyl, C₁₋₄-alkoxy, hydroxyl, amino, monoalkylamino having 1 to 4carbon atoms, and/or dialklyamino in which each alkyl group has 1 to 4carbon atoms.

Aryl, as a group or substituent per se or as part of a group orsubstituent, refers to an aromatic carbocyclic radical containing 6 to10 carbon atoms, unless indicated otherwise. Suitable aryl groupsinclude but are not limited to phenyl, napthyl and biphenyl. Substitutedaryl groups include the above-described aryl groups which aresubstituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro,methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino,hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl,alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, and acyloxy (e.g.,acetoxy).

Heterocyclic groups refer to saturated, partially saturated and fullyunsaturated heterocyclic groups having one, two or three rings and atotal number of 5 to 10 ring atoms wherein at least one of the ringatoms is an N, O or S atom. Preferably, the heterocyclic group contains1 to 3 hetero-ring atoms selected from N, O and S. Suitable saturatedand partially saturated heterocyclic groups include, but are not limitedto dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl,tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,isoxazolinyl and the like. Suitable heteroaryl groups include but arenot limited to furyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl,imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl,naphthyridinyl and the like. Other examples of suitable heterocyclicgroups, are 2-furyl, 3-furyl, 2-quinolinyl, 1,3-benzodioxyl, 2-thienyl,3-thienyl, 1,3-thiazoly-2-yl, 1,3-oxazol-2-yl, pyrrolidin-1-yl,piperidin-1-yl, morpholin-4-yl, 2-benzofuranyl, 2-benzothiophenyl,3-thienyl, 2,3-dihydro-5-benzofuranyl, 4-indoyl, 4-pyridyl,3-quinolinyl, 4-quinolinyl, 1,4-benzodioxan-6-yl, 3-indoyl, 2-pyrrolyl,tetrahydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, 5-indolyl,1,5-benzoxepin-8-yl, 3-pyridyl, 6-coumarinyl, 5-benzofuranyl,2-isoimidazol-4-yl, 3-pyrazolyl, and 3-carbazolyl.

Substituted heterocyclic groups refer to the heterocyclic groupsdescribed above, which are substituted in one or more places by, forexample, halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro,oxo, amino, alkylamino, and dialkylamino.

Radicals that are substituted one or more times preferably have 1 to 3substituents, especially 1 or 2 substituents of the exemplifiedsubstituents. Halogenated radicals such as halogenated alkyls arepreferably fluorinated and include but are not limited to perhaloradicals such as trifluoromethyl.

According to a further aspect of the invention, in the compounds ofFormulas I-IV, when R is NR⁶R⁷, at least one of R⁶ and R⁷ is alkylhaving 2 to 4 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms,cycloalkyl having 3 to 7 carbon atoms, or cycloalkylalkyl having 4 to 7carbon atoms, or R⁶ and R⁷ together are an alkylene group containing 4-6carbon atoms which forms a ring with the N atom.

According to a further aspect of the invention, in the compounds ofFormulas I-IV, R is not NR⁶R⁷.

According to a further aspect of the invention, in the compounds ofFormulas I-IV, A is a radical according to formulas (a), (b) or (c), andat least one of R¹, R³, or R⁴ is H, F, Cl, Br, I, OH, CN, nitro, NH₂,COH, NR⁶R⁷, carboxy, CONR⁶R⁷, NR²COR⁸, NR²COOR⁸, NR²CSR⁸, NR²CONR²R⁹,NR²CSNR²R⁹, NR²SO₂R¹⁰, NR²CONR⁶R⁷, NR²CSNR⁶R⁷, NR²R⁹, SO₂R¹⁰, SOR¹⁰,alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbonatoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbonatoms, wherein the alkyl, fluorinated alkyl, alkenyl, or alkynyl groupsare in each unsubstituted or substituted by Ar or Het, cycloalkyl having3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms,cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, cycloalkoxy having3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms,alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, fluorinatedhydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms,monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein eachalkyl group independently has 1 to 4 carbon atoms, alkoxycarbonyl having2 to 6 carbon atoms, Ar, Het, OAr, or OHet; or is of one of thefollowing formulas

and/or

R² is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, orcycloalkylalkyl having 4 to 7 carbon atoms; and/or

Het is a heterocyclic group, which is fully saturated, partiallysaturated or fully unsaturated, having 5 to 10 ring atoms in which atleast 1 ring atom is a N, O or S atom, which is unsubstituted orsubstituted one or more times by halogen, aryl having 6 to 10 carbonatoms and is optionally substituted, alkyl having 1 to 8 C atoms, alkoxyhaving 1 to 8 C atoms, cyano, trifluoromethyl, nitro, oxo, OH,alkoxycarbonylalkyl having 3 to 8 carbon atoms, amino, monoalkylaminohaving 1 to 8 C atoms, dialkylamino wherein each alkyl group has 1 to 8C atoms, SO₂R¹¹, —CXR¹¹, piperidinylethyl or combinations thereof.

According to a further aspect of the invention, in the compounds ofFormulas I-IV, at least one of R¹, R³, or R⁴ is

COH, NR⁶R⁷ wherein at least one of R⁶ and R⁷ is other than alkyl,carboxy, CONR⁶R⁷, NR²COR⁸, NR²COOR⁸, NR²CSR⁸, NR²CONR²R⁹, NR²CSNR²R⁹,NR²SO₂R¹⁰, NR²CONR⁶R⁷, NR²CSNR⁶R⁷, NR²R⁹, SO₂R¹⁰, SOR¹⁰, alkyl having 1to 4 carbon atoms which is substituted by Ar or Het, fluorinated alkylhaving 1 to 4 carbon atoms which is substituted by Ar or Het, alkenylhaving 2 to 6 carbon atoms which is optionally substituted by Ar or Het,alkynyl having 2 to 6 carbon atoms which is optionally substituted by Aror Het, cycloalkenyl having 5 to 8 carbon atoms, cycloalkenylalkylhaving 6 to 9 carbon atoms, fluorinated hydroxyalkyl having 1 to 4carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, OAr, OHet, orHet which is substituted by SO₂R¹¹ or —CXR¹¹, or

is selected from the following formulas

and/or

R⁵ is carboxy, alkoxycarbonyl having 2 to 6 carbon atoms, CONR⁶R⁷,NR²COR⁸, NR²CSR⁸, NR²CONR²R⁹, NR²CSNR²R⁹, NR²SO₂R¹⁰, NR²CONR⁶R⁷,NR²CSNR⁶R⁷, NR²R⁹, SO₂R¹⁰, SOR¹⁰, alkenyl having 2 to 6 carbon atoms,alkynyl having 2 to 6 carbon atoms (e.g., ethynyl, propynyl), alkylsubstituted by Ar or Het, alkenyl substituted by Ar or Het, alkynylsubstituted by Ar or Het (e.g., phenylacetylene), cycloalkenyl having 5to 8 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms,fluorinated hydroxyalkyl having 1 to 4 carbon atoms (e.g.,2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl), fluorinatedhydroxyalkoxy having 2 to 4 carbon atoms, OAr, OHet, or Het which issubstituted by SO₂R¹¹ or —CXR¹¹.

According to a further aspect of the invention, in the compounds ofFormulas I-IV, at least one of R¹, R³, R⁴, and R⁵ is

carboxy, alkoxycarbonyl having 2 to 6 carbon atoms, CONR⁶R⁷, NR²COR⁸,NR²CSR⁸, NR²CONR²R⁹, NR²CSNR²R⁹, NR²SO₂R¹⁰, NR²CONR⁶R⁷, NR²CSNR⁶R⁷,NR²R⁹, SO₂R¹⁰, SOR¹⁰, alkenyl having 2 to 6 carbon atoms, alkynyl having2 to 6 carbon atoms (e.g., ethynyl, propynyl), alkyl substituted by Aror Het, alkenyl substituted by Ar or Het, alkynyl substituted by Ar orHet (e.g., phenylacetylene), cycloalkenyl having 5 to 8 carbon atoms,cycloalkenylalkyl having 6 to 9 carbon atoms, fluorinated hydroxyalkylhaving 1 to 4 carbon atoms (e.g.,2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl), fluorinatedhydroxyalkoxy having 2 to 4 carbon atoms, OAr, OHet, or Het which issubstituted by SO₂R¹¹ or —CXR¹¹(Preferably, at least one of R¹, R³, R⁴,and R⁵ is alkynyl having 2 to 6 carbon atoms, fluorinated hydroxyalkylhaving 1 to 4 carbon atoms, or Ar-alkynyl (e.g., phenylacetylene),especially R¹ or R⁴.);

R⁶ and Rare each, independently, H, alkyl having 1 to 4 carbon atoms,cycloalkyl having 3 to 7 carbon atoms, or cycloalkylalkyl having 4 to 7carbon atoms, or R⁶ and R⁷ together are an alkylene group containing 4-6carbon atoms which forms a ring with the N atom;

R⁹ is Ar or Het; and

Het is a heterocyclic group, which is fully saturated, partiallysaturated or fully unsaturated, having 5 to 10 ring atoms in which atleast 1 ring atom is a N, O or S atom, which is unsubstituted orsubstituted one or more times by halogen (F, Cl, Br, or I, preferably For Cl), aryl having 6 to 10 carbon atoms (e.g., phenyl, naphthyl,biphenyl) and is optionally substituted, alkyl having 1 to 8 C atoms,alkoxy having 1 to 8 C atoms, cyano, trifluoromethyl, nitro, oxo, amino,monoalkylamino having 1 to 8 C atoms, dialkylamino wherein each alkylgroup has 1 to 8 C atoms, SO₂R¹¹, —CXR¹¹, or combinations thereof.

According to a further aspect of the invention, the compounds areselected from formula I in which A is of formulae (a) or (c), X is O, R²is H or alkyl (e.g., CH₃), and R¹ and R⁴ are each F, Cl, CN, NO₂, NH₂,fluorinated alkyl (e.g., CF₃), alkoxy (e.g., OCH₃), fluorinated alkoxy(e.g., OCF₃), fluorinated hydroxyalkyl (e.g.,2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl), alkynyl (e.g.,ethynyl, propynyl), cycloalkyl, cycloalkylalkoxy, Ar, Ar-alkynyl (e.g.,phenylacetylene), or Het. For example, R¹ and R⁴ are each selected fromF, Cl, CN, NO₂, NH₂, CF₃, OCH₃, OC₂H₅, OCF₃,2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl, ethynyl, propynyl,pentynyl, cyclopentyl, cyclohexyl, cyclopropylmethoxy, phenyl,phenylethynyl, dihydropyranyl (e.g., 3,6-dihydro-2H-pyran-4-yl),thiazolyl (e.g., 1,3-thiazol-2-yl), oxazolyl (e.g., 1,3-oxazol-2-yl),pyrrolidinyl (e.g., pyrrolidin-1-yl), piperidinyl (e.g. piperidin-1-yl),or morpholinyl (e.g. morpholin-4-yl). R⁴ can also be selected from CN,alkoxy, fluorinated alkoxy, and cycloalkylalkoxy, such as CN, OCH₃,OC₂H₅, OCF₃, and cyclopropylmethoxy.

According to a further aspect of the invention, the compounds areselected from formulae Ia or Ij wherein R² is H or alkyl (e.g., CH₃),and R¹ and R⁴ are each F, Cl, CN, NO₂, NH₂, fluorinated alkyl (e.g.,CF₃), alkoxy (e.g., OCH₃), fluorinated alkoxy (e.g., OCF₃), fluorinatedhydroxyalkyl (e.g.,2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl), alkynyl (e.g.,ethynyl, propynyl), cycloalkyl, cycloalkylalkoxy, Ar, Ar-alkynyl (e.g.,phenylacetylene), or Het. For example, R¹ and R⁴ are each selected fromF, Cl, CN, NO₂, NH₂, CF₃, OCH₃, OC₂H₅, OCF₃,2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl, ethynyl, propynyl,pentynyl, cyclopentyl, cyclohexyl, cyclopropylmethoxy, phenyl,phenylethynyl, dihydropyranyl (e.g., 3,6-dihydro-2H-pyran-4-yl),thiazolyl (e.g., 1,3-thiazol-2-yl), oxazolyl (e.g., 1,3-oxazol-2-yl),pyrrolidinyl (e.g., pyrrolidin-1-yl), piperidinyl (e.g. piperidin-1-yl),or morpholinyl (e.g. morpholin-4-yl). R⁴ can also be selected from CN,alkoxy, fluorinated alkoxy, and cycloalkylalkoxy, such as CN, OCH₃,OC₂H₅, OCF₃, and cyclopropylmethoxy.

According to a further aspect of the invention, in the compounds ofFormulas I-IV, at least one R¹, R³ or R⁴ is COH, NR⁶R⁷ wherein at leastone of R⁶ and R⁷ is other than alkyl, or NR²COOR⁸.

According to a further aspect of the invention, in the compounds ofFormulas I-IV, at least one R¹, R³ or R⁴ is selected from the followingformulas

According to a further aspect of the invention, the compounds ofFormulas I-IV, exhibit 2-3 of substituents R¹, R³, or R⁴.

According to a further aspect of the invention, in the compounds ofFormulas I-IV, R² is fluorinated alkyl having 1 to 4 carbon atoms.

According to a further aspect of the invention, in the compounds ofFormulas I-IV, at least one R⁶ and R⁷ is alkoxyalkyl having 2 to 8carbon atoms.

According to a further aspect of the invention, in the compounds ofFormulas I-IV, the compound exhibits at least one R⁹ group that isAr-alkyl wherein the alkyl portion has 1 to 4 carbon atoms.

According to a further aspect of the invention, in the compounds ofFormulas I-IV, the compound exhibits at least one Het that is aheterocyclic group, which is fully saturated, partially saturated orfully unsaturated, having 5 to 10 ring atoms in which at least 1 ringatom is a N, O or S atom, and which is substituted by at least onesubstituent selected from OH, alkoxycarbonylalkyl having 3 to 8 carbonatoms, and piperidinylethyl.

According to a further compound and/or method aspect of the invention,the compound of formulas I-IV is selected from (wherein compounds intheir salt forms can also be in their non-salt forms):

-   3-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazole-6-carboxylic    acid hydroformate,-   3-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazole-6-carboxylic    acid,-   6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclohex-1-en-1-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclohex-1-en-1-yl)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyclopentyl-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide    hydrochloride,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxamide,-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-phenoxy-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-phenoxy-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-piperidin-1-yl-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-piperidin-1-yl-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-pyrrolidin-1-yl-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydrochloride,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisothiazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(pent-1-yn-1-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(pent-1-yn-1-yl)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(phenylethynyl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(phenylethynyl)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzisothiazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethyl)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide    hydrotrifluoroacetate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclopentyl-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-fluoro-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide    hydrochloride,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-morpholin-4-yl-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-piperidin-1-yl-1H-indazole-3-carboxamide    hydrotrifluoroacetate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-piperidin-1-yl-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-pyrrolidin-1-yl-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide    hydrochloride,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyclopentyl-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide,

N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxamidehydroformate,

-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-nitro-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydrochloride,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisothiazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(morpholin-4-yl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(prop-1-yn-1-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(prop-1-yn-1-yl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzisothiazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethyl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclopentyl-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-fluoro-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-nitro-1H-indazole-3-carboxamide,    and physiologically acceptable salts thereof.

According to a further compound and/or method aspect of the invention,the compound of formulas I-IV is selected from (wherein compounds intheir salt forms can also be in their non-salt forms):

-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-methyl-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-ethyl-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-cyclopentyl-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(nitro)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-hydroxytetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-hydroxytetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-(trifluoromethoxy)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-(trifluoromethoxy)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(hydroxy)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(hydroxy)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-(nitro)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-4-bromo-5-methoxy-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-bromo-5-methoxy-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-4-nitro-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(nitro)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(nitro)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(hydroxy)-1,2-benzisothiazole-3-carboxamide,-   N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(formyl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(hydroxymethyl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclopentylamino)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(3-thienyl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(2-thienyl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(2-thienyl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(propyl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(ethyl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(butyl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-cyclopropyl-5-methoxy-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-ethyl-5-methoxy-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(methyl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydrofuran-3-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(2-methoxyethyl)amino]-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1H-pyrrol-1-yl)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1H-pyrrol-1-yl)-1H-indazole-3-carboxamide,-   5-Amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide,-   5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide,-   4-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide,-   6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide,-   6-Amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide,-   7-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylmethyl)amino]-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(4-methoxyphenyl)acetyl]amino}-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(trifluoroacetyl)amino]-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(ethylsulfonyl)amino]-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(methylsulfonyl)amino]-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(ethylsulfonyl)amino]-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(ethylsulfonyl)amino]-1,2-benzisothiazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(ethylsulfonyl)amino]-1,2-benzisothiazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(methylsulfonyl)amino]-1,2-benzisothiazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(methylsulfonyl)amino]-1,2-benzisothiazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-[(methylsulfonyl)amino]-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(benzylsulfonyl)amino]-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(2,6-dichlorophenyl)ethyl]amino}carbonyl)amino]-1,2-benzisothiazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3-cyanophenyl)amino]carbonyl}amino)-1,2-benzisothiazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(4-florophenyl)ethyl]amino}carbonyl)amino]-1,2-benzisothiazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3,4-dimethylphenyl)amino]carbonyl}amino)-1,2-benzisothiazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2,5-dimethylphenyl)amino]carbonyl}amino)-1,2-benzisothiazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-methylbenzyl)amino]carbonyl}amino)-1,2-benzisothiazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(4-methylphenyl)ethyl]amino}carbonyl)amino]-1,2-benzisothiazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(3-methoxyphenyl)ethyl]amino}carbonyl)amino]-1,2-benzisothiazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(cyclopentylamino)carbonyl]amino}-1,2-benzisothiazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(propylamino)carbonyl]amino}-1,2-benzisothiazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(3-methoxybenzyl)amino]carbonyl}amino)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(cyclopentylamino)carbonyl]amino}-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(3-methoxybenzyl)amino]carbonyl}amino)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(propylamino)carbonyl]amino}-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(cyclopentylamino)carbonyl]amino}-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-ylamino)-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1H-1,2,3-triazol-4-yl)-1H-indazole-3-carboxamide    dihydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[1-(2-piperidin-1-ylethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole-3-carboxamide    dihydroformate,-   Ethyl[4-(3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-6-yl)-1H-1,2,3-triazol-1-yl]acetate    hydroformate,-   Benzyl(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl)carbamate,-   Vinyl(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl)carbamate,    and    physiologically acceptable salts thereof.

According to a further compound and/or method aspect of the invention,the compound of formulas I-IV is selected from (wherein compounds intheir salt forms can also be in their non-salt forms):

-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-methoxy-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-bromo-6-methoxy-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1,8-dihydropyrrolo[3,2-g]indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-benzyl-6-(difluoromethoxy)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(3-thienyl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(difluoromethoxy)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(difluoromethoxy)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-methoxy-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-6-methoxy-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-fluoro-5-methoxy-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy)-1H-indazole-3-carboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyclopropyl-6-methoxy-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-5-(3-thienyl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-yl]-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydrochloride,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(methyloxy)pyrrolidin-1-yl]-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(hydroxy)pyrrolidin-1-yl]-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(1-methylpyrrolidin-3-yl)oxy]-1H-indazole-3-carboxamide    dihydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydrochloride,-   N-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide    hydroformate,-   N-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-6-methoxy-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclopropylmethoxy)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclopentyloxy)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2,2,2-trifluoroethoxy)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2,2,2-trifluoroethoxy)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(benzyloxy)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yloxy)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2,3-dihydro-1H-inden-2-yloxy)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[2-(dimethylamino)ethoxy]-1H-indazole-3-carboxamide    dihydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-pyrrolidin-1-ylethoxy)-1H-indazole-3-carboxamide    dihydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(ethyl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-(ethyl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(cyclopropylmethyl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(dimethylamino)methyl]-1H-indazole-3-carboxamide    dihydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(diethylamino)methyl]-1H-indazole-3-carboxamide    dihydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(pyrrolidin-1-yl)methyl]-1H-indazole-3-carboxamide    dihydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(1-benzylpyrrolidin-3-yl)oxy]-1H-indazole-3-carboxamide    dihydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-ethyl-6-methoxy-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-ethyl-5-trifluoromethoxy-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-6-methoxy-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-5-trifluoromethoxy-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydrochloride,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2,2,2]oct-3-yl]-1-cyclopropylmethyl-5    (1,3-thiazol-2-yl)-1H-indazole-3-carboxamide hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethyl)-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-formylcyclohex-1-en-1-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(2-methoxyethoxy)propoxy]-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-cyclohexylpiperazin-1-yl)-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-ethylpiperazin-1-yl)-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[4-(3-furoyl)piperazin-1-yl]-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-ethoxypyrrolidin-1-yl)-1,2-benzisothiazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-ethoxypyrrolidin-1-yl)-1,2-benzisothiazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-methoxypyrrolidin-1-yl)-1,2-benzisothiazole-3-carboxamide,-   6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamide,-   5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxamide,-   5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-1H-indazole-3-carboxamide,-   5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-1H-indazole-3-carboxamide,-   6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-1H-indazole-3-carboxamide,-   Methyl    4-[(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl)amino]butanoate    dihydroformate,-   Methyl    4-[(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-6-yl)amino]butanoate    dihydroformate,-   tert-Butyl{2-[(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1,2-benzisothiazol-6-yl)amino]ethyl}propylcarbamate    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(1,3-thiazol-2-ylmethyl)amino]-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(dimethylamino)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2-methoxyethyl)-5-[(2-methoxyethyl)amino]-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[2-(diethylamino)-2-oxoethyl]amino}-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(butylamino)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylmethyl)amino]-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(dimethylamino)-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(diethylamino)-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1-(cyclopropylmethyl)-1H-indazole-3-carboxamide,-   5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(trifluoroacetyl)-1H-indazole-3-carboxamide    dihydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylcarbonyl)-5-[(cyclopropylcarbonyl)amino]-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-[(4-methoxyphenyl)acetyl]-5-{[(4-methoxyphenyl)acetyl]amino}-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1,2-benzisothiazole-3-carboxamide    hydroformate,-   6-(Acetylamino)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(dimethylamino)sulfonyl]amino}-1,2-benzisothiazole-3-carboxamide    hydroformate,-   5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(benzylsulfonyl)-1H-indazole-3-carboxamide    dihydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-6-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamide,-   N(3)-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-(3-methoxybenzyl)-5-({[(3-methoxybenzyl)amino]carbonyl}amino)-1H-indazole-1,3-dicarboxamide,-   N(3)-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-(4-fluorobenzyl)-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-1,3-dicarboxamide,-   N(3)-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-cyclopentyl-5-{[(cyclopentylamino)carbonyl]amino}-1H-indazole-1,3-dicarboxamide    hydroformate,-   N(3)-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-propyl-5-{[(propylamino)carbonyl]amino}-1H-indazole-1,3-dicarboxamide,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(cyclopropylmethyl)amino]carbonothioyl}amino)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(cyclopropylmethyl)amino]carbonothioyl}amino)-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(propylmethylamino)carbonothioyl]amino}-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(tert-butylamino)carbonothioyl]amino}-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(sec-butylamino)carbonyl]amino}-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamide    hydroformate,

N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-5-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamidehydroformate,

-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethyl)-5-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-5-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamide    hydroformate,-   Isopropyl{3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl}carbamate    hydroformate,-   Isopropyl{3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-[(isopropylamino)carbonyl]-1H-indazol-5-yl}carbamate    hydroformate,-   N-[(3S)-1-Oxido-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1H-indazole-3-carboxamide    hydrobromide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamide    hydrobromide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(diethylamino)carbonyl]amino}-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(pyrrolidin-1-ylcarbonyl)amino]-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(pyrrolidin-1-ylcarbonyl)amino]-1H-indazole-3-carboxamide    hydroformate,

N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxopyrrolidin-1-yl)-1,2-benzisothiazole-3-carboxamidehydroformate,

-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-oxopyrrolidin-1-yl)-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxo-4-phenylpyrrolidin-1-yl)-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxoimidazolidin-1-yl)-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-oxoimidazolidin-1-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-oxo-3-propylimidazolidin-1-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[2-(propylamino)ethyl]amino}-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methyl-2-oxoimidazolidin-1-yl)-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-isopropyl-2-oxoimidazolidin-1-yl)-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-propyl-2-oxoimidazolidin-1-yl)-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1,2-benzisoxazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisoxazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-methyl-2-oxoimidazolidin-1-yl)-1,2-benzisothiazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-isopropyl-2-oxoimidazolidin-1-yl)-1,2-benzisothiazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-propyl-2-oxoimidazolidin-1-yl)-1,2-benzisothiazole-3-carboxamide,-   6-[Acetyl(methyl)amino]-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[methyl(propionyl)amino]-1,2-benzisothiazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-N-methyl-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-yl]-1-ethyl-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1-ethyl-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1-cyclopropylmethyl-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2-methoxyethyl)-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(tetrahydrofuran-3-yl)-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-yl]-1-(cyclopropylmethyl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(benzyloxy)pyrrolidin-1-yl]-1-ethyl-1H-indazole-3-carboxamide    hydroformate,-   tert-Butyl    3-[3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-6-(1,3-thiazol-2-yl)-1H-indazol-1-yl]pyrrolidine-1-carboxylate    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-pyrrolidin-3-yl-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1-(2-thienylmethyl)-1H-indazole-3-carboxamide    hydroformate,-   N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2-phenoxyethyl)-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide    hydroformate,    and    physiologically acceptable salts thereof.

Preferred aspects include pharmaceutical compositions comprising acompound of this invention and a pharmaceutically acceptable carrierand, optionally, another active agent as discussed below; a method ofstimulating or activating inhibiting alpha-7 nicotinic receptors, e.g.,as determined by a conventional assay or one described herein, either invitro or in vivo (in an animal, e.g., in an animal model, or in a mammalor in a human); a method of treating a neurological syndrome, e.g., lossof memory, especially long-term memory, cognitive impairment or decline,memory impairment, etc. method of treating a disease state modulated bynicotinic alpha-7 activity, in a mammal, e.g., a human, e.g., thosementioned herein.

The compounds of the present invention may be prepared conventionally.Some of the known processes that can be used are described below. Allstarting materials are known or can be conventionally prepared fromknown starting materials.

Acids that were used in the preparation of the bicyclobase amide werecommercially available or were prepared by known procedures described inthe literature or as described below. For example, indazole-3-carboxylicacid was commercially available. Positional isomers of indazolecarboxylic acid were prepared from the requisite bromo-2-methylanilinesby diazotization followed by metal-halogen exchange and trapping withcarbon dioxide (Se e.g., DeLucca, G. V. Substituted2H-1,3-Diazapin-2-one Useful as an HIV Protease Inhibitor, U.S. Pat. No.6,313,110 B1, Nov. 6, 2001; and Sun, J. H.; Teleha, C. A.; Yan, J. S.;Rodgers, J. D.; Nugiel, D. A. Efficient Synthesis of 5-(Bromomethyl)-and 5-(Aminomethyl)-1-THP-Indazole. J. Org. Chem. 1997, 62, 5627-5629).A variety of the simple substituted indazole-3-acids, such as thebromoindazole acids, were prepared from the corresponding isatins bybasic hydrolysis, diazotization, and reduction (Snyder, H. R.; et al. J.Am. Chem. Soc. 1952, 74, 2009).

Some substituted indazole-3-acids were prepared by modifying existingindazole acids or esters. For example, 5-nitroindazole-3-acid wasprepared by nitration of indazole-3-acid (Kamm, O.; Segur, J. B. Org.Syn. Coll. Vol 1. 1941, 372). 6-Nitroindazole-3-acid was prepared from3-iodo-6-nitroindazole using copper (I) cyanide followed by hydrolysis.Some non-aromatic heterocyclic derivatives were prepared from thebromides by metal-halogen exchange, trapping of indazole aryllithiumswith ketones, followed by reduction or acid mediated elimination.Trapping of the indazole aryllithiums with amides provided ketones andaldehydes that served as useful precursors for, among other things,reductive aminations. Aromatic substituted indazole-3-acids wereprepared from the bromides via palladium mediated cross-coupling withboronic acids or aryl zinc reagents (Reeder, M. R.; et. al. Org. Proc.Res. Devel. 2003, 7, 696). 4-Bromo-5-methoxyindazole- and7-bromo-6-methoxyindazole-3-carboxylic acids were prepared from thecorresponding methoxyindazole-3-carboxylates by bromination andsaponification. 4-Fluoro-5-methoxyindazole- and7-fluoro-6-methoxyindazole-3-carboxylic acids were prepared from thecorresponding methoxyindazole-3-carboxylates by fluorination andsaponification. 5-Bromo-4-nitroindazole- and6-bromo-7-nitroindazole-3-carboxylic acids were prepared from thecorresponding bromoindazole-3-carboxylates by nitration andsaponification. Subjecting the nitro bromides to hydrogenolysis provided4-aminoindazole- and 7-aminoindazole-3-carboxylic acids. Theaminoindazole esters were transformed to additional useful acid analogsby reductive amination, alkylation, and acylation strategies.N-1-Alkylated indazole-3-carboxylic acids were prepared from thecorresponding indazole esters by standard alkylation procedures.N-1-Arylated indazole-3-carboxylic acids were prepared from thecorresponding indazole esters by copper mediated cross couplings withboronic acids. Phenol derivatives were prepared from the correspondingmethoxy acids using boron tribromide.

Some substituted indazole-3-acids were prepared from simple benzenederivatives. For example, 5-difluoromethoxyindazole-3-acid was preparedfrom 3-bromo-4-nitrophenol by reaction with ethyl difluoroacetate,reaction with diethyl malonate, decarboxylative saponification,esterification, reduction of the nitro group, and diazotization.6-Difluoromethoxyindazole-3-acid was prepared in a similar manner from2-bromo-5-difluoromethoxynitrobenzene. The2-bromo-5-difluoromethoxynitrobenzene used in that preparation wasprepared from 4-nitrophenol by ether formation, nitro reduction withconcomitant protection as the amide, nitration, amide hydrolysis, and aSandmeyer reaction with copper (I) bromide.6-Benzyloxyindazole-3-carboxylic acid and ester was prepared from4-methoxynitrobenzene by nitro reduction with concomitant protection asthe amide, nitration, amide hydrolysis, Sandmeyer reaction with copper(I) bromide, and demethylation. The phenol was alkylated with benzylbromide and the arylbromide was subjected to reaction with diethylmalonate, decarboxylative saponification, esterification, reduction ofthe nitro group, and diazotization. The 5-benzyloxy analog was preparedin a similar manner from 4-benzyloxy-2-bromonitrobenzene (Parker, K. A.;Mindt, T. L. Org. Lett. 2002, 4, 4265.) The benzyl group was removed byhydrogenolysis and the resulting phenol was transformed to etherderivatives via either alkylation or Mitsunobu reaction conditions.4-Methoxyindazole acid was prepared from 4-methoxyaniline by amideformation, nitration, amide hydrolysis, Sandmeyer reaction with copper(I) bromide, nitro reduction, isatin formation and rearrangement to theindazole, followed by hydrogenolytic removal of the bromine.

The benzisoxazole-, benzisoxazole-, and benzothiazolecarboxylic acidswere prepared using similar strategies outlined for the indazole acids.For example, ethyl 6-bromobenzisoxazole-3-carboxylate was prepared from2,5-dibromonitrobenzene by reaction with diethyl malonate,saponification and decarboxylation, and reaction with isoamylnitrite.Ethyl benzisoxazole-3-carboxylate was obtained by hydrogenolysis of the6-bromo derivative. 4-Benzothiazolecarboxylic acid was prepared from2-amino-4-chloro-benzothiazole by reaction with isoamyl nitrite followedby metal-halogen exchange and trapping with carbon dioxide.5-Benzothiazolecarboxylic acid was prepared from 4-chloro-3-nitrobenzoicacid by reaction with Na₂S and sodium hydroxide followed by reductionwith zinc in formic acid. 3-Benzisothiazolecarboxylic acid was preparedfrom thiophenol by reaction with oxalyl chloride and aluminum chloridefollowed by treatment with hydroxylamine, hydrogen peroxide, and sodiumhydroxide.

The bicycloamines, 3-aminoquinuclidine and the R- and S-enantiomersthereof, used in the preparation of the bicyclobase amides werecommercially available. The N-alkylated quinuclidines were prepared byacylation of 3-aminoquinuclidine followed by reduction of the amide.3-Aminomethylquinuclidine was prepared from 3-quinuclidinone by theaction of p-tolylsulfonylmethyl isocyanide followed by hydrogenation ofthe nitrile.

The bicyclobase amides were prepared from the acids and thebicycloamines using standard peptide coupling agents, such as HBTU,HATU, or HOBt and EDCI, or by converting the acids to the correspondingacid chloride and then reaction with the bicycloamine (Macor, J. E.;Gurley, D.; Lanthorn, T.; Loch, J.; Mack, R. A.; Mullen, G.; Tran, O.;Wright, N.; and J. E. Macor et al., “The 5-HT3-Antagonwast Tropisetron(ICS 205-930) was a Potent and Selective α-7 Nicotinic Receptor PartialAgonist,” Bioorg. Med. Chem. Lett. 2001, 9, 319-321). The couplings weregenerally performed at room temperatures for 18-24 hours. The resultantadducts were isolated and purified by standard techniques, such aschromatography or recrystallization, practiced by those skilled in theart.

One of ordinary skill in the art will recognize that compounds ofFormulas I-IV can exist in different tautomeric and geometrical isomericforms. All of these compounds, including cis isomers, trans isomers,diastereomic mixtures, racemates, nonracemic mixtures of enantiomers,substantially pure, and pure enantiomers, are within the scope of thepresent invention. Substantially pure enantiomers contain no more than5% w/w of the corresponding opposite enantiomer, preferably no more than2%, most preferably no more than 1%.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, dibenzoyltartaric,ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomerscan be separated into their individual diastereomers on the basis oftheir physical and/or chemical differences by methods known to thoseskilled in the art, for example, by chromatography or fractionalcrystallization. The optically active bases or acids are then liberatedfrom the separated diastereomeric salts. A different process forseparation of optical isomers involves the use of chiral chromatography(e.g., chiral HPLC columns), with or without conventional derivation,optimally chosen to maximize the separation of the enantiomers. Suitablechiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD andChiracel OJ among many others, all routinely selectable. Enzymaticseparations, with or without derivitization, are also useful. Theoptically active compounds of Formulas I-IV can likewise be obtained byutilizing optically active starting materials in chiral synthesisprocesses under reaction conditions which do not cause racemization.

In addition, one of ordinary skill in the art will recognize that thecompounds can be used in different enriched isotopic forms, e.g.,enriched in the content of ²H, ³H, ¹¹C, ¹³C and/or ¹⁴C. In oneparticular embodiment, the compounds are deuterated. Such deuteratedforms can be made the procedure described in U.S. Pat. Nos. 5,846,514and 6,334,997. As described in U.S. Pat. Nos. 5,846,514 and 6,334,997,deuteration can improve the efficacy and increase the duration of actionof drugs.

Deuterium substituted compounds can be synthesized using various methodssuch as described in: Dean, Dennis C.; Editor. Recent Advances in theSynthesis and Applications of Radiolabeled Compounds for Drug Discoveryand Development. [In: Curr., Pharm. Des., 2000; 6(10)] (2000), 110 pp.CAN 133:68895 AN 2000:473538 CAPLUS; Kabalka, George W.; Varma, RajenderS. The synthesis of radiolabeled compounds via organometallicintermediates. Tetrahedron (1989), 45(21), 6601-21, CODEN: TETRABISSN:0040-4020. CAN 112:20527 AN 1990:20527 CAPLUS; and Evans, E.Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem.(1981), 64(1-2), 9-32. CODEN: JRACBN ISSN:0022-4081, CAN 95:76229 AN1981:476229 CAPLUS.

Where applicable, the present invention also relates to useful forms ofthe compounds as disclosed herein, such as pharmaceutically acceptablesalts or prodrugs of all the compounds of the present invention forwhich salts or prodrugs can be prepared. Pharmaceutically acceptablesalts include those obtained by reacting the main compound, functioningas a base, with an inorganic or organic acid to form a salt, forexample, salts of hydrochloric acid, sulfuric acid, phosphoric acid,methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid,succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid,tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonicacid. Pharmaceutically acceptable salts also include those in which themain compound functions as an acid and is reacted with an appropriatebase to form, e.g., sodium, potassium, calcium, magnesium, ammonium, andcholine salts. Those skilled in the art will further recognize that acidaddition salts of the claimed compounds may be prepared by reaction ofthe compounds with the appropriate inorganic or organic acid via any ofa number of known methods. Alternatively, alkali and alkaline earthmetal salts can be prepared by reacting the compounds of the inventionwith the appropriate base via a variety of known methods.

The following are further examples of acid salts that can be obtained byreaction with inorganic or organic acids: acetates, adipates, alginates,citrates, aspartates, benzoates, benzenesulfonates, bisulfates,butyrates, camphorates, digluconates, cyclopentanepropionates,dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides,hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates,methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates,palmoates, pectinates, persulfates, 3-phenylpropionates, picrates,pivalates, propionates, succinates, tartrates, thiocyanates, tosylates,mesylates and undecanoates.

Preferably, the salts formed are pharmaceutically acceptable foradministration to mammals. However, pharmaceutically unacceptable saltsof the compounds are suitable as intermediates, for example, forisolating the compound as a salt and then converting the salt back tothe free base compound by treatment with an alkaline reagent. The freebase can then, if desired, be converted to a pharmaceutically acceptableacid addition salt.

The compounds of the invention can be administered alone or as an activeingredient of a formulation. Thus, the present invention also includespharmaceutical compositions of compounds of Formulas I-IV, containing,for example, one or more pharmaceutically acceptable carriers.

Numerous standard references are available that describe procedures forpreparing various formulations suitable for administering the compoundsaccording to the invention. Examples of potential formulations andpreparations are contained, for example, in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (currentedition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman andSchwartz, editors) current edition, published by Marcel Dekker, Inc., aswell as Remington's Pharmaceutical Sciences (Arthur Osol, editor),1553-1593 (current edition).

In view of their alpha-7 stimulating activity and, preferably their highdegree of selectivity, the compounds of the present invention can beadministered to anyone needing stimulation of alpha-7 receptors.Administration may be accomplished according to patient needs, forexample, orally, nasally, parenterally (subcutaneously, intraveneously,intramuscularly, intrasternally and by infusion) by inhalation,rectally, vaginally, topically and by ocular administration.

Various solid oral dosage forms can be used for administering compoundsof the invention including such solid forms as tablets, gelcaps,capsules, caplets, granules, lozenges and bulk powders. The compounds ofthe present invention can be administered alone or combined with variouspharmaceutically acceptable carriers, diluents (such as sucrose,mannitol, lactose, starches) and excipients known in the art, includingbut not limited to suspending agents, solubilizers, buffering agents,binders, disintegrants, preservatives, colorants, flavorants, lubricantsand the like. Time release capsules, tablets and gels are alsoadvantageous in administering the compounds of the present invention.

Various liquid oral dosage forms can also be used for administeringcompounds of the inventions, including aqueous and non-aqueoussolutions, emulsions, suspensions, syrups, and elixirs. Such dosageforms can also contain suitable inert diluents known in the art such aswater and suitable excipients known in the art such as preservatives,wetting agents, sweeteners, flavorants, as well as agents foremulsifying and/or suspending the compounds of the invention. Thecompounds of the present invention may be injected, for example,intravenously, in the form of an isotonic sterile solution. Otherpreparations are also possible.

Suppositories for rectal administration of the compounds of the presentinvention can be prepared by mixing the compound with a suitableexcipient such as cocoa butter, salicylates and polyethylene glycols.Formulations for vaginal administration can be in the form of a pessary,tampon, cream, gel, paste, foam, or spray formula containing, inaddition to the active ingredient, such suitable carriers as are knownin the art.

For topical administration the pharmaceutical composition can be in theform of creams, ointments, liniments, lotions, emulsions, suspensions,gels, solutions, pastes, powders, sprays, and drops suitable foradministration to the skin, eye, ear or nose. Topical administration mayalso involve transdermal administration via means such as transdermalpatches.

Aerosol formulations suitable for administering via inhalation also canbe made. For example, for treatment of disorders of the respiratorytract, the compounds according to the invention can be administered byinhalation in the form of a powder (e.g., micronized) or in the form ofatomized solutions or suspensions. The aerosol formulation can be placedinto a pressurized acceptable propellant.

The compounds can be administered as the sole active agent or incombination with other pharmaceutical agents such as other agents usedin the treatment of cognitive impairment and/or memory loss, e.g., otherα-7 agonists, PDE4 inhibitors, calcium channel blockers, muscarinic m1and m2 modulators, adenosine receptor modulators, amphakines NMDA-Rmodulators, mGluR modulators, dopamine modulators, serotonin modulators,canabinoid modulators, and cholinesterase inhibitors (e.g., donepezil,rivastigimine, and glanthanamine). In such combinations, each activeingredient can be administered either in accordance with their usualdosage range or a dose below their usual dosage range.

The compounds of the invention can be used in conjunction with “positivemodulators” which enhance the efficacy of nicotinic receptor agonists.See, e.g., the positive modulators disclosed in WO 99/56745, WO01/32619, and WO 01/32622. Such combinational therapy can be used intreating conditions/diseases associated with reduced nicotinictransmission.

Further the compounds may be used in conjunction with compounds thatbind to Aβ peptides and thereby inhibit the binding of the peptides toα7nACh receptor subtypes. See, e.g., WO 99/62505.

The present invention further includes methods of treatment that involveactivation of α-7 nicotinic receptors. Thus, the present inventionincludes methods of selectively activating/stimulating α-7 nicotinicreceptors in a patient (e.g., a mammal such as a human) wherein suchactivation/stimulation has a therapeutic effect, such as where suchactivation may relieve conditions involving neurological syndromes, suchas the loss of memory, especially long-term memory. Such methodscomprise administering to a patient (e.g., a mammal such as a human) inneed thereof, an effective amount of a compound of Formulas I-IV, aloneor as part of a formulation, as disclosed herein.

In accordance with a method aspect of the invention, there is provided amethod of treating a patient (e.g., a mammal such as a human) sufferingfrom a disease state (e.g., memory impairment) comprising administeringto the patient a compound according to Formulas I-IV. Preferably, thedisease state involves decreased nicotinic acetylcholine receptoractivity.

In accordance with a method aspect of the invention there is provided amethod for the treatment or prophylaxis of a disease or conditionresulting from dysfunction of nicotinic acetylcholine receptortransmission in a patient (e.g., a mammal such as a human) comprisingadministering an effective amount of a compound according to FormulasI-IV.

In accordance with a method aspect of the invention there is provided amethod for the treatment or prophylaxis of a disease or conditionresulting from defective or malfunctioning nicotinic acetylcholinereceptors, particularly α7nACh receptors, in a patient (e.g., a mammalsuch as a human) comprising administering an effective amount of acompound according to Formulas I-IV.

In accordance with a method aspect of the invention there is provided amethod for the treatment or prophylaxis of a disease or conditionresulting from suppressed nicotinic acetylcholine receptor transmissionin a patient (e.g., a mammal such as a human) comprising administeringan amount of a compound according to Formulas I-IV effective to activateα7nACh receptors.

In accordance with another method aspect of the invention there isprovided a method for the treatment or prophylaxis of a psychoticdisorder, a cognition impairment (e.g., memory impairment), orneurodegenerative disease in a patient (e.g., a mammal such as a human)comprising administering an effective amount of a compound according toFormulas I-IV.

In accordance with another method aspect of the invention there isprovided a method for the treatment or prophylaxis of a disease orcondition resulting from loss of cholinergic synapses in a patient(e.g., a mammal such as a human) comprising administering an effectiveamount of a compound according to Formulas I-IV.

In accordance with another method aspect of the invention there isprovided a method for the treatment or prophylaxis of aneurodegenerative disorder by activation of α7nACh receptors in apatient (e.g., a mammal such as a human) comprising administering aneffective amount of a compound according to Formulas I-IV.

In accordance with another method aspect of the invention there isprovided a method for protecting neurons in a patient (e.g., a mammalsuch as a human) from neurotoxicity induced by activation of α7nAChreceptors comprising administering an effective amount of a compoundaccording to Formulas I-IV.

In accordance with another method aspect of the invention there isprovided a method for the treatment or prophylaxis of aneurodegenerative disorder by inhibiting the binding of Aβ peptides toα7nACh receptors in a patient (e.g., a mammal such as a human)comprising administering an effective amount of a compound according toFormulas I-IV.

In accordance with another method aspect of the invention there isprovided a method for protecting neurons in a patient (e.g., a mammalsuch as a human) from neurotoxicity induced by Aβ peptides comprisingadministering an effective amount of a compound according to FormulasI-IV.

In accordance with another method aspect of the invention there isprovided a method for alleviating inhibition of cholinergic functioninduced by Aβ peptides in a patient (e.g., a mammal such as a human)comprising administering an effective amount of a compound according toFormulas I-IV.

A subject or patient in whom administration of the therapeutic compoundis an effective therapeutic regimen for a disease or disorder ispreferably a human, but can be any animal, including a laboratory animalin the context of a clinical trial or screening or activity experiment.Thus, as can be readily appreciated by one of ordinary skill in the art,the methods, compounds and compositions of the present invention areparticularly suited to administration to any animal, particularly amammal, and including, but by no means limited to, humans, domesticanimals, such as feline or canine subjects, farm animals, such as butnot limited to bovine, equine, caprine, ovine, and porcine subjects,wild animals (whether in the wild or in a zoological garden), researchanimals, such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats,etc., avian species, such as chickens, turkeys, songbirds, etc., i.e.,for veterinary medical use.

The compounds of the present invention are nicotinic alpha-7 ligands,preferably agonists, especially partial agonists, for the alpha-7nicotinic acetylcholine receptor. Assays for determining nicotinicacetylcholine activity are known within the art. See, e.g., Davies, A.R., et al., Characterisation of the binding of [3H]methyllycaconitine: anew radioligand for labelling alpha 7-type neuronal nicotinicacetylcholine receptors. Neuropharmacology, 1999. 38(5): p. 679-90. Asagonists for α7nACh receptors, the compounds are useful in theprophylaxis and treatment of a variety of diseases and conditionsassociated with the central nervous system. Nicotinic acetylcholinereceptors are ligand-gastrol ion-channel receptors that are composed offive subunit proteins which form a central ion-conducting pore.Presently, there are eleven known neuronal nACh receptor subunits (α2-α9and β2-(β4). There are also five further subunits expressed in theperipheral nervous system (α1, β1, γ, δ, ε).

The nACh receptor subtypes can be homopentameric or heteropentameric.The subtype which has received considerable attention is thehomopentameric α7 receptor subtype formed from five α7 subunits. Theα7nACh receptors exhibit a high affinity for nicotine (agonist) and forα-bungarotoxin (antagonist). Studies have shown the α7nACh receptoragonists can be useful in the treatment of psychotic diseases,neurodegenerative diseases, and cognitive impairments, among otherthings. While nicotine is a known agonist, there is a need for thedevelopment of other α7nACh receptor agonists, especially selectiveagonists, which are less toxic or exhibit fewer side effects thannicotine.

The compound anabaseine, i.e., 2-(3-pyridyl)-3,4,5,6-tetrahydropyridineis a naturally occurring toxin in certain marine worms (nemertine worms)and ants. See, e.g., Kem et al., Toxicon, 9:23, 1971. Anabaseine is apotent activator of mammalian nicotinic receptors. See, e.g., Kem, Amer.Zoologist, 25, 99, 1985. Certain anabaseine analogs such as anabasineand DMAB(3-[4-(dimethylamino)benzylidene]-3,4,5,6-tetrahydro-2′,3′-bipyridine)are also known nicotinic receptor agonists. See, e.g., U.S. Pat. No.5,602,257 and WO 92/15306. One particular anabaseine analog,(E-3-[2,4-dimethoxy-benzylidene]-anabaseine, also known as GTS-21 andDMXB (see, e.g., U.S. Pat. No. 5,741,802), is a selective partial α7nAChreceptor agonist that has been studied extensively. For example,abnormal sensory inhibition is a sensory processing deficit inschizophrenics and GTS-21 has been found to increase sensory inhibitionthrough interaction with α7nACh receptors. See, e.g., Stevens et al.,Psychopharmacology, 136: 320-27 (1998).

Another compound which is known to be a selective α7nACh receptoragonist is Tropisetron, i.e., 1αH, 5αH-tropan-3α-ylindole-3-carboxylate. See J. E. Macor et al., The 5-HT3-AntagonistTropisetron (ICS 205-930) is a Potent and Selective A7 NicotinicReceptor Partial Agonist. Bioorg. Med. Chem. Lett. 2001, 319-321).

Agents that bind to nicotinic acetylcholine receptors have beenindicated as useful in the treatment and/or prophylaxis of variousdiseases and conditions, particularly psychotic diseases,neurodegenerative diseases involving a dysfunction of the cholinergicsystem, and conditions of memory and/or cognition impairment, including,for example, schizophrenia, anxiety, mania, depression, manic depression[examples of psychotic disorders], Tourette's syndrome, Parkinson'sdisease, Huntington's disease [examples of neurodegenerative diseases],cognitive disorders (such as Alzheimer's disease, Lewy Body Dementia,Amyotrophic Lateral Sclerosis, memory impairment, memory loss, cognitiondeficit, attention deficit, Attention Deficit Hyperactivity Disorder),and other uses such as treatment of nicotine addiction, inducing smokingcessation, treating pain (i.e., analgesic use), providingneuroprotection, and treating jetlag. See, e.g., WO 97/30998; WO99/03850; WO 00/42044; WO 01/36417; Holladay et al., J. Med. Chem.,40:26, 4169-94 (1997); Schmitt et al., Annual Reports Med. Chem.,Chapter 5, 41-51 (2000); Stevens et al., Psychopharmatology, (1998) 136:320-27; and Shytle et al., Molecular Psychiatry, (2002), 7, pp. 525-535.

Thus, in accordance with the invention, there is provided a method oftreating a patient, especially a human, suffering from psychoticdiseases, neurodegenerative diseases involving a dysfunction of thecholinergic system, and conditions of memory and/or cognitionimpairment, including, for example, schizophrenia, anxiety, mania,depression, manic depression [examples of psychotic disorders],Tourette's syndrome, Parkinson's disease, Huntington's disease [examplesof neurodegenerative diseases], and/or cognitive disorders (such asAlzheimer's disease, Lewy Body Dementia, Amyotrophic Lateral Sclerosis,memory impairment, memory loss, cognition deficit, attention deficit,Attention Deficit Hyperactivity Disorder) comprising administering tothe patient an effective amount of a compound according to FormulasI-IV.

Neurodegenerative disorders included within the methods of the presentinvention include, but are not limited to, treatment and/or prophylaxisof Alzheimer's diseases, Pick's disease, diffuse Lewy Body disease,progressive supranuclear palsy (Steel-Richardson syndrome), multisystemdegeneration (Shy-Drager syndrome), motor neuron diseases includingamyotrophic lateral sclerosis, degenerative ataxias, cortical basaldegeneration, ALS-Parkinson's-Dementia complex of Guam, subacutesclerosing panencephalitis, Huntington's disease, Parkinson's disease,synucleinopathies, primary progressive aphasia, striatonigraldegeneration, Machado-Joseph disease/spinocerebellar ataxia type 3,olivopontocerebellar degenerations, Gilles De La Tourette's disease,bulbar, pseudobulbar palsy, spinal muscular atrophy, spinobulbarmuscular atrophy (Kennedy's disease), primary lateral sclerosis,familial spastic paraplegia, Werdnig-Hoffmann disease,Kugelberg-Welander disease, Tay-Sach's disease, Sandhoff disease,familial spastic disease, Wohlfart-Kugelberg-Welander disease, spasticparaparesis, progressive multifocal leukoencephalopathy, prion diseases(such as Creutzfeldt-Jakob, Gerstmann-Sträussler-Scheinker disease, Kuruand fatal familial insomnia), and neurodegenerative disorders resultingfrom cerebral ischemia or infarction including embolic occlusion andthrombotic occlusion as well as intracranial hemorrhage of any type(including, but not limited to, epidural, subdural, subarachnoid andintracerebral), and intracranial and intravertebral lesions (including,but not limited to, contusion, penetration, shear, compression andlaceration).

In addition, α7nACh receptor agonists, such as the compounds of thepresent invention can be used to treat age-related dementia and otherdementias and conditions with memory loss including age-related memoryloss, senility, vascular dementia, diffuse white matter disease(Binswanger's disease), dementia of endocrine or metabolic origin,dementia of head trauma and diffuse brain damage, dementia pugilisticaand frontal lobe dementia. See, e.g., WO 99/62505. Thus, in accordancewith the invention, there is provided a method of treating a patient,especially a human, suffering from age-related dementia and otherdementias and conditions with memory loss comprising administering tothe patient an effective amount of a compound according to FormulasI-IV.

Thus, in accordance with a further embodiment, the present inventionincludes methods of treating patients suffering from memory impairmentdue to, for example, mild cognitive impairment due to aging, Alzheimer'sdisease, schizophrenia, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeld-Jakob disease, depression, aging, headtrauma, stroke, CNS hypoxia, cerebral senility, multiinfarct dementiaand other neurological conditions, as well as HIV and cardiovasculardiseases, comprising administering an effective amount of a compoundaccording to Formulas I-IV.

Amyloid precursor protein (APP) and Aβ peptides derived therefrom, e.g.,Aβ₁₋₄₀, Aβ₁₋₄₂, and other fragments, are known to be involved in thepathology of Alzhemier's disease. The Aβ₁₋₄₂ peptides are not onlyimplicated in neurotoxicity but also are known to inhibit cholinergictransmitter function. Further, it has been determined that Aβ peptidesbind to α7nACh receptors. Thus, agents which block the binding of the Aβpeptides to α-7 nAChRs are useful for treating neurodegenerativediseases. See, e.g., WO 99/62505. In addition, stimulation α7nAChreceptors can protect neurons against cytotoxicity associated with Aβpeptides. See, e.g., Kihara, T. et al., Ann. Neurol., 1997, 42, 159.

Thus, in accordance with an embodiment of the invention there isprovided a method of treating and/or preventing dementia in anAlzheimer's patient which comprises administering to the subject atherapeutically effective amount of a compound according to FormulasI-IV to inhibit the binding of an amyloid beta peptide (preferably,Aβ₁₋₄₂) with nACh receptors, preferable α7nACh receptors, mostpreferably, human α7nACh receptors (as well as a method for treatingand/or preventing other clinical manifestations of Alzheimer's diseasethat include, but are not limited to, cognitive and language deficits,apraxias, depression, delusions and other neuropsychiatric symptoms andsigns, and movement and gait abnormalities).

The present invention also provides methods for treating otheramyloidosis diseases, for example, hereditary cerebral angiopathy,normeuropathic hereditary amyloid, Down's syndrome, macroglobulinemia,secondary familial Mediterranean fever, Muckle-Wells syndrome, multiplemyeloma, pancreatic- and cardiac-related amyloidosis, chronichemodialysis anthropathy, and Finnish and Iowa amyloidosis.

In addition, nicotinic receptors have been implicated as playing a rolein the body's response to alcohol ingestion. Thus, agonists for α7nAChreceptors can be used in the treatment of alcohol withdrawal and inanti-intoxication therapy. Thus, in accordance with an embodiment of theinvention there is provided a method of treating a patient for alcoholwithdrawal or treating a patient with anti-intoxication therapycomprising administering to the patient an effective amount of acompound according to Formulas I-IV.

Agonists for the α7nACh receptor subtypes can also be used forneuroprotection against damage associated with strokes and ischemia andglutamate-induced excitotoxicity. Thus, in accordance with an embodimentof the invention there is provided a method of treating a patient toprovide for neuroprotection against damage associated with strokes andischemia and glutamate-induced excitotoxicity comprising administeringto the patient an effective amount of a compound according to FormulasI-IV.

As noted above, agonists for the α7nACh receptor subtypes can also beused in the treatment of nicotine addiction, inducing smoking cessation,treating pain, and treating jetlag, obesity, diabetes, and inflammation.Thus, in accordance with an embodiment of the invention there isprovided a method of treating a patient suffering from nicotineaddiction, pain, jetlag, obesity and/or diabetes, or a method ofinducing smoking cessation in a patient comprising administering to thepatient an effective amount of a compound according to Formulas I-IV.

The inflammatory reflex is an autonomic nervous system response to aninflammatory signal. Upon sensing an inflammatory stimulus, theautonomic nervous system responds through the vagus nerve by releasingacetylcholine and activating nicotinic α7 receptors on macrophages.These macrophages in turn release cytokines. Dysfunctions in thispathway have been linked to human inflammatory diseases includingrheumatoid arthritis, diabetes and sepsis. Macrophages express thenicotinic α7 receptor and it is likely this receptor that mediates thecholinergic anti-inflammatory response. Therefore, compounds withaffinity for the α7nACh receptor on macrophages may be useful for humaninflammatory diseases including rheumatoid arthritis, diabetes andsepsis. See, e.g., Czura, C J et al., J. Intern. Med., 2005, 257(2),156-66.

Thus, in accordance with an embodiment of the invention there isprovided a method of treating a patient (e.g., a mammal, such as ahuman) suffering from an inflammatory disease, such as, but not limitedto, rheumatoid arthritis, diabetes or sepsis, comprising administeringto the patient an effective amount of a compound according to FormulasI-IV.

In addition, due to their affinity to α7nACh receptors, labeledderivatives of the compounds of Formulas I-IV (e.g., C¹¹ or F¹⁸ labeledderivatives), can be used in neuroimaging of the receptors within, e.g.,the brain. Thus, using such labeled agents in vivo imaging of thereceptors can be performed using, e.g., PET imaging.

The condition of memory impairment is manifested by impairment of theability to learn new information and/or the inability to recallpreviously learned information. Memory impairment is a primary symptomof dementia and can also be a symptom associated with such diseases asAlzheimer's disease, schizophrenia, Parkinson's disease, Huntington'sdisease, Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovasculardisease, and head trauma as well as age-related cognitive decline.

Thus, in accordance with an embodiment of the invention there isprovided a method of treating a patient suffering from, for example,mild cognitive impairment (MCI), vascular dementia (VaD), age-associatedcognitive decline (AACD), amnesia associated w/open-heart-surgery,cardiac arrest, and/or general anesthesia, memory deficits from earlyexposure of anesthetic agents, sleep deprivation induced cognitiveimpairment, chronic fatigue syndrome, narcolepsy, AIDS-related dementia,epilepsy-related cognitive impairment, Down's syndrome, Alcoholismrelated dementia, drug/substance induced memory impairments, DementiaPuglistica (Boxer Syndrome), and animal dementia (e.g., dogs, cats,horses, etc.) comprising administering to the patient an effectiveamount of a compound according to Formulas I-IV.

The dosages of the compounds of the present invention depend upon avariety of factors including the particular syndrome to be treated, theseverity of the symptoms, the route of administration, the frequency ofthe dosage interval, the particular compound utilized, the efficacy,toxicology profile, pharmacokinetic profile of the compound, and thepresence of any deleterious side-effects, among other considerations.

The compounds of the invention can be administered to patients, e.g.,mammals, particularly humans, at typical dosage levels customary for α-7nicotinic receptor agonists such as the known α-7 nicotinic receptoragonist compounds mentioned above. For example, the compounds can beadministered, in single or multiple doses, by oral administration at adosage level of, for example, 0.0001-10 mg/kg/day, e.g., 0.01-10mg/kg/day. Unit dosage forms can contain, for example, 1-200 mg ofactive compound. For intravenous administration, the compounds can beadministered in single or multiple dosages.

In carrying out the procedures of the present invention it is of courseto be understood that reference to particular buffers, media, reagents,cells, culture conditions and the like are not intended to be limiting,but are to be read so as to include all related materials that one ofordinary skill in the art would recognize as being of interest or valuein the particular context in which that discussion is presented. Forexample, it is often possible to substitute one buffer system or culturemedium for another and still achieve similar, if not identical, results.Those of skill in the art will have sufficient knowledge of such systemsand methodologies so as to be able, without undue experimentation, tomake such substitutions as will optimally serve their purposes in usingthe methods and procedures disclosed herein.

The present invention will now be further described by way of thefollowing non-limiting examples. In applying the disclosure of theseexamples, it should be kept clearly in mind that other and differentembodiments of the methods disclosed according to the present inventionwill no doubt suggest themselves to those of skill in the relevant art.

In the foregoing and in the following examples, all temperatures are setforth uncorrected in degrees Celsius; and, unless otherwise indicated,all parts and percentages are by weight.

The entire disclosures of all applications, patents and publications,cited above and below, are hereby incorporated by reference.

Using the following procedures and further procedures described below,the following compounds in Examples 1-315 were prepared. Other synthesisexamples are described in U.S. patent application Ser. No. 10/669,645,hereby incorporated by reference.

EXAMPLES

All spectra were recorded at 300 MHz on a Bruker Instruments NMR unlessotherwise stated. Coupling constants (J) are in Hertz (Hz) and peaks arelisted relative to TMS (δ 0.00 ppm). Microwave reactions were performedusing a Personal Chemistry Optimizer™ microwave reactor in 2.5 mL or 5mL Personal Chemistry microwave reactor vials. All reactions wereperformed at 200° C. for 600 s with the fixed hold time ON unlessotherwise stated. Sulfonic acid ion exchange resins (SCX) were purchasedfrom Varian Technologies. Analytical HPLC was performed on 4.6 mm×100 mmXterra RP₁₈ 3.5μ columns using a gradient of 20/80 to 80/20 water (0.1%formic acid)/acetonitrile (0.1% formic acid) over 6 min. PreparativeHPLC was performed on 30 mm×100 mm Xtera Prep RP₁₈ 5μ columns using an 8min gradient of 95/5 to 20/80 water (0.1% formic acid)/acetonitrile(0.1% formic acid).

Acid Preparations.

The following procedures (1-27) detail the preparation of the indazole,benzothiazole, benzisothiazole, and benzisoxazole acids that were notcommercially available.

Procedure 1

Procedure 1 provides a method of preparation of 1,3-benzothiazolecarboxylic acids from chloro nitrobenzoic acids.

To a solution of 4-chloro-3-nitrobenzoic acid (99.2 mmol) inN,N-dimethylformamide (400 mL) was added potassium carbonate (254 mmol).After 30 min, ethyl iodide (119 mmol) was added and the reaction mixturewas heated at 50° C. for 4 h. Water (3 L) was added and the mixture wasextracted with diethyl ether (2×500 mL). The organic extracts werecombined, washed with brine (1 L), dried over anhydrous sodium sulfateand concentrated. The residue was crystallized from hexanes, thusproviding the ester in 86% yield. ¹H NMR (500 MHz, CDCl₃) δ 8.51 (d,1H), 8.17 (dd, 1H), 7.65 (d, 1H), 4.43 (q, 2H), 1.42 (t, 3H).

Sulfur (49.91 mmol) was dissolved in a solution of sodium sulfidenonahydrate (49.96 mmol) in water (60 mL). This solution was combinedwith a solution of ethyl 4-chloro-3-nitrobenzoate (85.36 mmol) inethanol (100 mL) and the resulting mixture was heated at reflux for 3 h.The hot reaction mixture was poured into water (600 mL) and maintainedfor 15 min. The product was isolated by filtration and recrystallizedfrom ethanol, thus providing the disulfide in 77% yield. ¹H NMR (500MHz, CDCl₃) δ 8.96 (d, 1H), 8.19 (dd, 1H), 7.88 (d, 1H), 4.43 (q, 2H),1.41 (t, 3H).

A mixture of diethyl 4,4′-dithiobis(3-nitrobenzoate) (24.8 mmol) andzinc granules (234 mmol) in formic acid (600 mL) was heated to refluxfor 48 h. The mixture was allowed to cool to room temperature andconcentrated to dryness. The residue was partitioned between ethylacetate (500 mL) and saturated aqueous sodium bicarbonate (500 mL). Theorganic layer was separated, dried over anhydrous sodium sulfate andconcentrated. The residue was chromatographed on neutral Alumina (1/1 to0/1 hexanes/dichloromethane), thus providing the thiazole in 51% yield.¹H NMR (500 MHz, CDCl₃) δ 9.08 (s, 1H), 8.83 (d, 1H), 8.14 (dd, 1H),8.02 (d, 1H), 4.45 (q, 2H), 1.44 (t, 3H); MS (EI) m/z 208 (M⁺+1).

To a solution of ethyl 1,3-benzothiazole-5-carboxylate (25.6 mmol) in amixture of methanol (150 mL), tetrahydrofuran (40 mL) and water (5 mL)was added a 50% aqueous solution of sodium hydroxide (10 mL). Themixture was maintained at rt for 18 h and was concentrated. The residuewas partitioned between water (300 mL) and diethyl ether (200 mL) andthe organic layer was removed. Concentrated hydrochloric acid was addedto the aqueous layer to adjust the pH to 4 and the mixture was extractedwith ethyl acetate (3×300 mL). The combined extracts were washed withbrine (200 mL), dried over anhydrous sodium sulfate, and concentratedthus providing the acid in 94% yield.

The following acids were prepared using this method:

-   1,3-benzothiazole-5-carboxylic acid-   1,3-benzothiazole-6-carboxylic acid

Procedure 2

Procedure 2 provides a method for the preparation of1,3-benzothiazole-7-carboxylic acid from ethyl 3-aminobenzoate.

A solution of ethyl 3-aminobenzoate (90 mmol) in chlorobenzene (100 mL)was cooled to −10° C. and treated with sulfuric acid (45 mmol),dropwise. After 15 min, solid potassium thiocyanate (95 mmol) was addedin several portions over 30 min followed by 18-crown-6 (250 mg). Themixture was heated at 100° C. for 10 h, allowed to cool to rt, and wasmaintained for an additional 4 h. The precipitated solids were isolatedby filtration and were washed successively with chlorobenzene (25 mL)and hexanes (3×100 mL). The solid was suspended in water (300 mL) andthe suspension was maintained 30 min. The product was isolated byfiltration and washed with water (2×100 mL). The product was dried in avacuum oven (55° C.) for 16 h, thus providing the thiocarbamate in 69%yield. ¹H NMR (500 MHz, Me₂SO-d₆) δ 1.32 (t, J=7.5, 3H), 4.32 (q, J=7,2H), 7.44-7.47 (m, 2H), 7.68-7.76 (m, 3H), 8.05 (s, 1H), 9.86 (s, 1H);MS (APCI) m/z 225 (M⁺+1).

A solution of thiocarbamate (12.2 mmol) in chloroform (10 mL) was addeddropwise over a period of 40 min to a vigorously maintained mixture ofethyl 3-[(aminocarbonothioyl)amino]benzoate (5.78 mmol), glacial aceticacid (10 mL) and chloroform (10 mL). The mixture was maintained 30 minat rt and then was heated at 70° C. for 4 h. The mixture was allowed tocool to room temperature and maintained for an additional 13 h. Thevolatiles were removed under reduced pressure and the solid residue wassuspended in a mixture of chloroform (10 mL) and acetone (10 mL). Theproduct was isolated by filtration, washed successively with acetone (5mL) and hexanes (10 mL), and dried in a vacuum oven, thus providing theproduct in 95% yield as a mixture of ethyl2-amino-1,3-benzothiazole-7-carboxylate hydrobromide and ethyl2-amino-1,3-benzothiazole-5-carboxylate hydrobromide in a ratio of 95/5,respectively. This product was partitioned between saturated aqueoussolution of sodium bicarbonate (25 mL) and a mixture of ethyl acetate(70 mL) and tetrahydrofuran (30 mL). The organic layer was separated,dried over anhydrous sodium sulfate and concentrated. The residue wascrystallized form ethyl acetate, thus providing pure ethyl2-amino-1,3-benzothiazole-7-carboxylate. ¹H NMR (500 MHz, Me₂SO-d₆) δ1.35 (t, J=7.5, 3H), 4.36 (q, J=7, 2H), 7.35 (t, J=7.5, 1H), 7.57 (d,J=7, 1H), 7.61 (bs, 2H), 7.65 (d, J=8, 1H); MS (EI) m/z 223 (M⁺+1).

iso-Amylnitrite (53 mmol) was added to a solution of ethyl2-amino-1,3-benzothiazole-7-carboxylate (5.40 g) in tetrahydrofuran (70mL) and the mixture was heated at reflux for 4 h. The volatiles wereremoved under reduced pressure and the residue was purified bychromatography (0/100 to 5/95 methanol/dichloromethane), thus providingthe ester in 71% yield. ¹H NMR (500 MHz, CDCl₃) δ 1.47 (t, J=7.5, 3H),4.49 (q, J=7, 2H), 7.62 (t, J=8, 1H), 8.20 (d, J=6.5, 1H), 8.33 (d, J=8,1H), 9.12 (s, 1H); MS (EI) m/z 208 (M⁺+1). A 50% aqueous sodiumhydroxide (10 mL) was added to a 0° C. solution of ethyl1,3-benzothiazole-7-carboxylate (16.89 mmol) in a mixture of methanol(65 mL), tetrahydrofuran (20 mL) and water (5 mL). The mixture wasmaintained at room temperature for 4 h and the volatiles were removedunder reduced pressure. The residue was dissolved in water (100 mL) andconcentrated hydrochloric acid was added to adjust the pH of thesolution to 5. The mixture was cooled to 0° C. and maintained for 30min. The product was isolated by filtration, washed with water (10 mL),and dried in vacuum oven (70° C.) for 16 h, thus providing the acid in91% yield. ¹H NMR (500 MHz, Me₂SO-d₆) δ 7.71 (t, J=7.5, 1H), 8.15 (d,J=7, 1H), 8.38 (d, J=8, 1H), 9.51 (s, 1H), 13.74 (bs, 1H); MS (APCI) m/z178 (M⁺−1).

-   Literature reference: Kunz et. al. U.S. Pat. No. 5,770,758.

Procedure 3

Procedure 3 provides a preparation of substitutedbenzisothiazole-3-carboxylic acids from the corresponding thiophenols.

To a solution of 3-methoxythiophenol (26.7 mmol) in ether (20 mL) wasadded oxalyl chloride (43 mmol) dropwise. The mixture was heated atreflux for 1.5 h, cooled to rt, and concentrated in vacuo. The resultingyellow oil was dissolved in dichloromethane (50 mL), cooled to 0° C.,and was treated with aluminum chloride (32.0 mmol) in portions. Themixture was heated at reflux for 30 min, cooled to rt, and poured ontoice water with stifling. The organic layer was separated andsuccessively washed with saturated, aqueous sodum bicarbonate, water,and brine. The organic layer was dried over magnesium sulfate, filteredand concentrated in vacuo. The residue was purified by chromatography(4/1 ethyl acetate/hexane), thus providing6-methoxy-1-benzothiophene-2,3-dione in 47% yield as an orange solid.

To a mixture of the dione (0.44 mmol) in 30% aqueous solution ofammonium hydroxide (2.0 mL) was added 35% aqueous solution hydrogenperoxide (0.2 mL) and the reaction mixture was maintained for 12 h. Theprecipitated pink solids were isolated by filtration, washed with water,and dried under high vacuum, thus providing the amide in 42% yield.

To a solution of the amide (5.46 mmol) in methanol (100 mL) was added 10N sodium hydroxide (12 mL). The mixture was heated at reflux for 12 h,cooled to rt, and was acidified to pH<2 by the slow addition of conc.hydrochloric acid. The organic layer was extracted with dichloromethane(2×) and was dried over sodium sulfate. The crude product was purifiedby chromatography (300/50/1 dichloromethane/methanol/formic acid), thusproviding the acid in 89% as a pink solid. LC/MS (EI) t_(R) 6.17 min,m/z 210 (M⁺+1).

The following acids were prepared by this method:

-   Benzisothiazole-3-carboxylic acid.-   6-Bromobenzisothiazole-3-carboxylic acid.-   5-Bromobenzisothiazole-3-carboxylic acid.-   6-Methoxybenzisothiazole-3-carboxylic acid-   7-Methoxybenzisothiazole-3-carboxylic acid.-   6-Trifluoromethoxybenzisothiazole-3-acid.-   6-Ethoxybenzisothiazole-3-acid.-   6-Cyclopropylmethoxybenzisothiazole-3-acid.

Procedure 4

Procedure 4 provides a method for the preparation of isatins fromanilines and the conversion of the isatins to the correspondingindazole-3-carboxylic acids.

A solution of the substituted aniline (565 mL) in 6N hydrochloric acid(106 mL) was added to a suspension of 2,2,2-trichloro-1-ethoxyethanol(678 mL) and sodium sulfate (3.15 mol) in water (1.4 L) and the reactionmixture was stirred vigorously for 1 h. A solution of hydroxylaminehydrochloride (2.08 mol) in water (650 mL) was added in one portion andthe reaction mixture was heated at 80° C. for 1.5 h. The reactionmixture was cooled to 10° C. and the precipitated solids were collectedby filtration, washed with water, and dried to provide the amide in 91%yield.

The amide was added to sulfuric acid (1.9 L) and the reaction mixturewas heated at 60° C. for 6 h. The reaction mixture was allowed to coolto room temperature and was cautiously poured onto ice (7 kg). Theprecipitated solids were collected by filtration, washed with water, anddried to provide the isatin in 61% yield.

The conversion of the substituted isatins to the correspondingindazole-3-carboxylic acids is essentially the same method as describedfor indazole-3-carboxylic acid: Snyder, H. R., et. al. J. Am. Chem. Soc.1952, 74, 2009. The substituted isatin (22.1 mmol) was diluted with 1 Nsodium hydroxide (24 mL) and was heated at 50° C. for 30 min. Theburgundy solution was allowed to cool to rt and was maintained for 1 h.The reaction mixture was cooled to 0° C. and was treated with a 0° C.solution of sodium nitrite (22.0 mmol) in water (5.5 mL). This solutionwas added through a pipet submerged below the surface of a vigorouslystirred solution of sulfuric acid (2.3 mL) in water (45 mL) at 0° C. Theaddition took 15 min and the reaction was maintained for an additional30 min. A cold (0° C.) solution of tin (II) chloride dihydrate (52.7mmol) in concentrated hydrochloric acid (20 mL) was added to thereaction mixture over 10 min and the reaction mixture was maintained for60 min. The precipitated solids were isolated by filtration, washed withwater, and dried to give a quantitative mass balance. This material wasof sufficient purity (¹H NMR and LC/MS) to use in the next step withoutfurther purification. Alternatively, the acid was recrystallized fromacetic acid to provide pure material.

The following acids were prepared using this method:

-   5-Chloro-1H-indazole-3-acid.-   7-Methoxy-1H-indazole-3-acid.-   5-Fluoro-1H-indazole-3-acid.-   6-Fluoro-1H-indazole-3-acid.-   5-Bromo-1H-indazole-3-acid.-   6-Bromo-1H-indazole-3-acid.-   5-Trifluoromethoxy-1H-indazole-3-acid.-   6-Trifluoromethyl-1H-indazole-3-acid.-   5-Methoxy-1H-indazole-3-acid.-   6-Methoxy-1H-indazole-3-acid.-   5-Methyl-1H-indazole-3-carboxylic acid.

Procedure 5

Procedure 5 provides a method for the preparation of bromoindazoles frombromomethylanilines.

Acetic anhydride (2.27 equiv.) was added to a cooled (0° C.) solution ofbromomethylaniline (1.00 equiv.) in chloroform (1.5 mL/mmol) whilemaintaining the temperature below 40° C. The reaction mixture wasallowed to warm to room temperature and was maintained for 1 h.Potassium acetate (0.29 eq) and isoamyl nitrite (2.15 equiv.) was addedand the reaction mixture was heated at reflux for 18 h. The volatileswere removed under reduced pressure. Water (0.65 L/mol) was added to theresidue and the mixture was concentrated. Concentrated hydrochloric acid(1 L/mol) was added to the residue and the mixture was heated at 50° C.for 2 h. The mixture was allowed to cool to room temperature and the pHwas adjusted to 10 by the slow addition of a 50% aqueous sodiumhydroxide solution. The mixture was diluted with water (0.65 L/mol) andwas extracted with ethyl acetate (2×1.2 L/mol). The combined extractswere washed with brine (1 L/mol) and dried over anhydrous sodiumsulfate. The organic solution was filtered through a plug of silica gel(ethyl acetate wash), concentrated, and the residue was triturated withheptane (1 L/mol). The solids were collected by filtration, rinsed withheptane, and dried in a vacuum oven, thus providing the brominatedindazole in 60-80% yield.

-   Literature reference: George V. DeLucca, U.S. Pat. No. 6,313,110.

The following indazoles were prepared using this method:

-   5-Bromo-1H-indazole.-   6-Bromo-1H-indazole.

Procedure 6

Procedure 6 provides a method for the preparation of indazole carboxylicacid from bromoindazole.

To a solution of bromoindazole (1.00 equiv.) in anhydroustetrahydrofuran (7 L/mol) at room temperature was added sodium hydride(60% in mineral oil, 1.11 equiv.) in several portions. The resultingsolution was maintained for 30 min at room temperature and was thencooled to −60° C. A 1.3 M solution of sec-butyllithium in cyclohexane(2.1 equiv.)

was added to the reaction mixture while maintaining the internaltemperature below −50° C. The mixture was maintained for an additional 2h at −50° C. A steady stream of anhydrous carbon dioxide was bubbledthrough the reaction mixture for 1 h. The flow was continued while thereaction mixture was allowed to warm to room temperature. Brine (6L/mol) was added and the pH of the mixture was adjusted to 5 withconcentrated hydrochloric acid. The mixture was extracted with warmethyl acetate (3×8 L/mol) and the combined extracts were washed withsmall volume of brine, dried over anhydrous sodium sulfate, andconcentrated. The residue was purified by chromatography on silica gelor by crystallization, thus providing the acid in 30-60% yield.

The following indazoles were prepared using this method:

-   1H-Indazole-5-carboxylic acid.-   1H-Indazole-6-carboxylic acid.

Procedure 7

Procedure 7 provides a preparation of 1H-indazole-7-carboxylic acid from2-amino-3-methylbenzoic acid.

To a solution of 2-amino-3-methylbenzoic acid (66.9 mmol) inN,N-dimethylformamide (200 mL) was added cesium carbonate (102 mmol).The mixture was stirred for 30 min.

A solution of methyl iodide (67.0 mmol) in N,N-dimethylformamide (50 mL)was added dropwise and the reaction mixture was maintained for 18 h atrt. The reaction mixture was partitioned between water (1 L) and ether(200 mL) and the water layer was extracted with an additional volume ofether (100 mL). The combined extracts were washed with brine (500 mL),dried over anhydrous potassium carbonate, and concentrated, thusproviding methyl 2-amino-3-methylbenzoate in 92% yield. ¹H NMR (400 MHz,CDCl₃) δ 7.77 (d, 1H), 7.19 (d, 1H), 6.59 (t, 1H), 5.82 (bs, 2H), 3.86(s, 3H), 2.17 (s, 3H).

To a solution of the ester (106 mmol) in chloroform (300 mL) was addedacetic anhydride (239 mmol) while maintaining the temperature below 40°C. The reaction mixture was maintained at room temperature for 1 h whenpotassium acetate (30.6 mmol) and isoamyl nitrite (228 mmol) was added.The reaction mixture was heated at reflux for 24 h and was allowed tocool to room temperature. The reaction mixture was washed with asaturated, aqueous solution of sodium bicarbonate, dried over sodiumsulfate, and concentrated. Methanol (100 mL) and 6 N hydrochloric acid(100 mL) were added to the residue and the mixture was maintained for 18h at rt. The volatiles were removed under reduced pressure and theresidue was triturated with ethyl acetate (100 mL). The product wasisolated by filtration, washed with ethyl acetate (20 mL), and dried,thus providing methyl 1H-indazole-7-carboxylate hydrochloride in 68%yield. ¹H NMR (500 MHz, Me₂SO-d₆) δ 13.3 (bs, 1H), 8.26 (d, 1H), 8.12(d, 1H), 8.25 (dd, 1H), 7.27 (t, 1H), 3.97 (s, 3H); MS (APCI) m/z 177(M⁺+1).

A solution of the indazole (33.0 mmol) in methanol (100 mL) at 0° C. wastreated with an 29% aqueous solution of potassium hydroxide (20 mL). Thereaction mixture was allowed to warm to rt and was maintained for 18 h.The pH of the solution was adjusted to 5.5 by the addition ofconcentrated hydrochloric acid and the volatiles were removed underreduced pressure. The residue was partitioned between brine (100 mL) andethyl acetate (200 mL) and the aqueous layer was extracted withadditional warm ethyl acetate (200 mL). The combined organic extractswere dried over anhydrous sodium sulfate and concentrated. The residuewas triturated with ethyl acetate (30 mL) and the solids were isolatedby filtration, thus providing the acid in 94% yield.

Procedure 8

Procedure 8 provides a method for the preparation of5-nitroindazole-3-acid from ethyl indazole-3-carboxylate.

Ethyl indazole-3-carboxylate (73.7 mmol) was dissolved in 20 mLconcentrated sulfuric acid and the reaction mixture was cooled to 0° C.A mixture of concentrated sulfuric acid (12 mL) and 70% nitric acid (12mL) was added dropwise over the course of 1 h. The mixture was stirredfor an additional 1 h at 0° C. and was poured onto of crushed ice (200g). The solid was collected by vacuum filtration, washed with severalportions of water and dried in vacuo. The dried solid was suspended in250 mL acetonitrile and the mixture was heated at reflux for 2 h. Themixture was allowed to cool to room temperature and the solid wascollected and dried in vacuo, thus providing ethyl5-nitroindazole-3-carboxylate in 53% yield as a colorless solid andethyl 7-nitroindazole-3-carboxylate (5%) as a colorless solid. Theesters were saponified using sodium hydroxide to provide the acids.

-   Literature reference: Org. Synthesis, Coll. Vol. 1, page 372.

The following acids were prepared using this method:

-   5-Nitro-1H-indazole-3-carboxylic acid.-   7-Nitro-1H-indazole-3-carboxylic acid.-   Ethyl 5-nitro-1H-indazole-3-carboxylate.-   Ethyl 7-nitro-1H-indazole-3-carboxylate.

Procedure 9

Procedure 9 provides a method for the preparation of6-nitroindazole-3-acid from 3-iodo-6-nitroindazole.

A 5 mL microwave reaction vessel was charged with 3-iodo-6-nitroindazole(1 mmol), copper (I) cyanide (2 mmol) and N,N-dimethylformamide (3 mL).The vessel was sealed and subjected to microwave irradiation at 185° C.for 600 sec. The reaction mixture was partitioned between ethyl acetate(100 mL) and water (100 mL) and the mixture was filtered through Celite.The organic layer was collected, washed with brine, dried (magnesiumsulfate), and concentrated to give 122 mg of a 10 to 1 mixture of3-cyano-6-nitroindazole and 6-nitroindazole as a yellow solid. The 10 to1 mixture of 3-cyano-6-nitroindazole and 6-nitroindazole was dissolvedin 10 N sodium hydroxide and the bright orange solution was heated at100° C. for 1 h. The mixture was allowed to cool to room temperature andcarefully acidified to pH 1 with 3 N hydrochloric acid. The solid wasisolated and triturated with EtOAc, thus providing 51 mg of6-nitroindazole-3-carboxylic acid as a brown solid.

-   3-Iodo-6-nitroindazole was prepared from 6-nitroindazole using the    method of Collot, V.; et. al. Tetrahedron 1999, 55, 6917.

Procedure 10

Procedure 10 provides a method for the trapping of indazole aryllithiumswith ketones and the coupling with 3-aminoquinuclidine to formheterocyclic derivatives.

tert-Butyl 6-bromoindazole-3-carboxylate was prepared from the acid byreaction with a 2-fold excess of di-tert-butyldicarbonate followed bytreatment with sodium hydroxide. To a suspension of sodium hydride (60%mineral oil dispersion) (4.8 mmol) in tetrahydrofuran (40 mL) at 0° C.was slowly added a solution of tert-butyl 6-bromoindazole-3-carboxylate(4.0 mmol) in tetrahydrofuran (4 mL). After stirring for 0.5 h at 0° C.,the mixture was cooled to −78° C. and a 1.7 M solution oftert-butyllithium in pentane (5.1 mmol) was added. After 0.5 h at −78°C., a solution of tetrahydropyran-4-one (5 mmol) in tetrahydrofuran (1mL) was added dropwise. The mixture was stirred at −78° C. for 1 h andwarmed to 0° C. The reaction mixture was quenched with saturated aqueousammonium chloride and the mixture was partitioned between ethyl acetate(100 mL) and water (100 mL). The organic layer was separated, washedwith brine (50 mL), dried (magnesium sulfate), and concentrated. Theresidue was purified by chromatography (70/30 ethyl acetate/hexanes) toyield 6-(4-hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acidtert-butyl ester (68%) as a colorless solid.

6-(4-Hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acidtert-butyl ester (0.86 mmol) was dissolved in trifluoroacetic acid (3mL) and the mixture was maintained at room temperature for 16 h. Thesolvent was removed in vacuo and the residue was triturated with ethylacetate to provide6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid (76%). Theacids were coupled with quinuclidine amine according to procedure A.

6-(4-Hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acidtert-butyl ester (1.0 mmol) was taken up in trifluoroacetic acid (5 mL),triethylsilane (2 mL), and dichloromethane (3 mL) and the mixture wasrefluxed for 16 h. The solvent was removed in vacuo and the residue wastriturated with ethyl acetate to provide6-(tetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid (60%) as a tansolid.

The following acids were prepared using this method:

-   6-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1H-indazole-3-carboxylic    acid.-   5-(4-Hydroxytetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid.-   6-(4-Hydroxytetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid.-   5-(3,6-Dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid.-   6-(3,6-Dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid.-   5-(Tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid.-   6-(Tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid.-   5-Formyl-1H-indazole-3-carboxylic acid.-   6-Formyl-1H-indazole-3-carboxylic acid.

Procedure 11

Procedure 11 provides a method for the preparation of4-bromo-5-methoxyindazole-3-carboxylic acid from ethyl5-methoxyindazole-3-carboxylate and describes further modifications toproduce 4-substituted 5-methoxyindazole-3-acids.

N-Bromosuccinimide (24.0 mmol) was added to a solution of ethyl5-methoxyindazole-3-carboxylate (20.0 mmol) in acetonitrile (200 mL).The reaction mixture was maintained for 16 h and was partitioned betweenwater (150 mL) and ethyl acetate (250 mL). The layers were separated andthe organic layer was washed with brine (50 mL), dried (magnesiumsulfate), and concentrated. The residue was purified by chromatographyusing a gradient of 90/10 to 70/30 hexanes/ethyl acetate, thus providingthe 4-brominated product in 57% yield and trace quantities of the6-brominated product. The 4-brominated ester was further derivatizedusing Suzuki (procedure G; 60-70% yields) or Negishi (procedure H;20-40% yields) reaction conditions described below. The ester (3.82mmol) was diluted with ethanol (10.0 mL) and 5 M sodium hydroxide (10.0mL) and the reaction mixture was maintained for 4 h at ambienttemperature. The reaction mixture was diluted with water (50 mL) andacidified to pH 1 with 6 N hydrochloric acid. The solids were collectedby filtration, thus providing the acids in 80-95% yield.

The following compounds were prepared by this method:

-   4-Bromo-5-methoxy-1H-indazole-3-carboxylic acid.-   6-Bromo-5-methoxy-1H-indazole-3-carboxylic acid.-   7-Bromo-6-methoxy-1H-indazole-3-carboxylic acid.-   5-Bromo-6-methoxy-1H-indazole-3-carboxylic acid.-   5-Methoxy-4-(thiophen-2-yl)-1H-indazole-3-carboxylic acid.-   5-Methoxy-4-(thiophen-3-yl)-1H-indazole-3-carboxylic acid.-   6-Methoxy-5-(thiophen-3-yl)-1H-indazole-3-carboxylic acid.-   5-Cyclopropyl-6-methoxy-1H-indazole-3-carboxylic acid.

Procedure 12

Procedure 12 provides a method for the preparation of5-bromo-4-nitroindazole-3-carboxylic acid from ethyl5-bromoindazole-3-carboxylate.

Ethyl 5-bromo-1H-indazole-3-carboxylate (5.02 mmol) was dissolved insulfuric acid (20.0 mL) and was cooled to 0° C. A mixture of 70% nitricacid (7/3, nitric acid/water, 1.0 mL) and sulfuric acid (2.0 mL) wasadded dropwise and the reaction was maintained for 1 hour at 0° C. Thereaction mixture was poured onto 100 mL of ice water and the solidscollected by filtration, thus providing the product in 86% yield. Theester (3.82 mmol) was diluted with ethanol (10.0 mL) and 5 M sodiumhydroxide (10.0 mL) and the reaction mixture was maintained for 4 h atambient temperature. The reaction mixture was diluted with water (50 mL)and acidified to pH 1 with 6 N hydrochloric acid. The solids werecollected by filtration, thus providing the acid in 82% yield

Procedure 13

Procedure 13 provides a method for the preparation of N-1-alkylatedindazole-3-carboxylic acids from the corresponding indazole ester.

To a solution of ethyl 5-methoxyindazole-3-carboxylate (1.50 mmol) inacetonitrile (15 mL) was added potassium carbonate (5.99 mmol) andmethyl iodide (3.00 mol). The reaction was heated at 60° C. for 4 hours,allowed to cool to ambient temperature, and was partitioned betweenwater (50 mL) and ethyl acetate (50 mL). The layers were separated andthe organic later was washed with brine (25 mL), dried (magnesiumsulfate), and concentrated. The residue was purified by chromatographyusing a gradient of 95/5 to 80/20 hexanes/ethyl acetate to provide the2-substituted indazole (17%) and the 1-substituted indazole (44%). The1-substituted indazole (61 mg, 0.26 mmol) was suspended in ethanol (5.0mL) and was warmed to facilitate dissolution. An aliquot of a 5.0 Msolution of sodium hydroxide in water (2.00 mL) was added and thereaction mixture was maintained at ambient temperature for 16 h. Thereaction mixture was diluted with water (50 mL) and was acidified with6.0 N hydrochloric acid. The aqueous layer was extracted with ethylacetate (3×50 mL) and the combined organic layers were washed with brine(25 mL), dried (magnesium sulfate), and concentrated, thus providing theacid in 95% yield.

The following compounds were prepared by this method:

-   5-Methoxy-1-methyl-1H-indazole-3-carboxylic acid.-   5-Methoxy-1-ethyl-1H-indazole-3-carboxylic acid.-   5-Methoxy-1-cyclopentyl-1H-indazole-3-carboxylic acid.-   5-Methoxy-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxylic acid.-   5-Bromo-1-methyl-1H-indazole-3-carboxylic acid.-   5-Bromo-1-ethyl-1H-indazole-3-carboxylic acid.-   5-Bromo-1-cyclopropylmethyl-1H-indazole-3-carboxylic acid.-   5-Bromo-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxylic acid.-   6-Bromo-1-methyl-1H-indazole-3-carboxylic acid.-   6-Bromo-1-ethyl-1H-indazole-3-carboxylic acid.-   6-Bromo-1-cyclopropylmethyl-1H-indazole-3-carboxylic acid.-   6-Bromo-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxylic acid.-   1-Benzyl-6-difluoromethoxy-1H-indazole-3-carboxylic acid.-   1-Benzyl-5-difluoromethoxy-1H-indazole-3-carboxylic acid.

Procedure 14

Procedure 14 provides a method for the demethylation of methoxyindazoleacids and the coupling with 3-aminoquinuclidine to formhydroxy-substituted derivatives.

The methoxy indazole acid (10.4 mmol) was diluted with dichloromethane(100 mL) and the solution was cooled to −78° C. A 1.0 M solution ofboron tribromide in dichloromethane (52 mmol, 5 eq.) was added dropwiseover 30 min. The reaction mixture was allowed to warm to roomtemperature and was maintained for 24 h. The reaction was slowlyquenched with MeOH (100 mL) and concentrated to dryness. The residue waspurified by chromatography using a gradient of hexane/ethyl acetate(100/0 to 80/20) followed by elution with a mixture of ethylacetate/methanol/triethylamine (70/30/1), thus providing the phenol(60-80%) as a brown solid. This procedure was also applied toN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamide,N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1H-indazole-3-carboxamide,and the benzisothiazole analogs with success.

The following compounds were prepared using this method:

-   5-Hydroxy-1H-indazole-3-carboxylic acid.-   6-Hydroxy-1H-indazole-3-carboxylic acid.-   5-Hydroxy-1,2-benzisothiazole-3-carboxylic acid.-   6-Hydroxy-1,2-benzisothiazole-3-carboxylic acid

Procedure 15:

Procedure 15 provides a method for the preparation of7-fluoro-6-methoxy-1H-indazole-3-carboxylic acid and4-fluoro-5-methoxy-1H-indazole-3-carboxylic acid from the correspondingmethoxyindazole acids.

1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (1.00 g, 2.82 mmol) was added to a solution ofethyl 6-methoxy-1H-indazole-3-carboxylate (500 mg, 2.27 mmol) inacetonitrile (15.0 mL) and the reaction mixture was maintained at rt for18 h. The reaction was partitioned between water (50 mL) and ethylacetate (50 mL) and the separated organic layer was washed with brine(25 mL), dried (magnesium sulfate), and concentrated. The residue waspurified by chromatography (95/5 to 80/20 hexanes/ethyl acetate) toyield 541 mg (23%) of the fluorinated ester. A solution of the ester(124 mg, 0.520 mmol) in ethanol (5.00 mL) was diluted with 5.0 M ofsodium hydroxide (2.00 mL) and the mixture was maintained at rt for 18h. The reaction was acidified with 6 N hydrochloric acid and partitionedbetween water (50 mL) and ethyl acetate (50 mL). The layers wereseparated and the organic washed with brine (25 mL), dried (magnesiumsulfate), and concentrated in vacuo to yield 109 mg (84%) of the acid.

The acid was coupled with the bicyclobase according to procedure A.

The following acid was prepared using this method:

-   7-Fluoro-6-methoxy-1H-indazole-3-carboxylic acid.-   4-Fluoro-5-methoxy-1H-indazole-3-carboxylic acid.

Procedure 16:

Procedure 16 details the preparation of ethylbenzisoxazole-3-carboxylate from 2,5-dibromonitrobenzene.

Diethyl malonate (12.6 g, 79 mmol) was added to a suspension of sodiumhydride (3.16 g, 132 mmol) in dimethylsulfoxide (60 ml) over 30 min. Thetemperature of the reaction rose to 60° C. and the mixture clarified.1,4-Dibromo-2-nitrobenzene (10 g, 36.0 mmol) was added and the solutionwas maintained for 2 h at 100° C. The reaction mixture was allowed tocool to rt and was poured into ice (300 g-400 g). The precipitatedsolids were isolated by filtration and dried to provide 11.0 g of theproduct (89%).

The ester (11.0 g, 32.0 mmol) was diluted with a 2 N solution of sodiumhydroxide (32 mL, 63 mmol) and the reaction mixture was maintained atroom temperature for 16 h. The aqueous layer was extracted withdichloromethane (20 mL) and was acidified. The precipitated solids wereisolated by filtration and dried to provide 7.00 g of the acid (89%).

Sulfuric acid (1 mL) was added to a solution of the acid (7.00 g, 27.0mmol) in ethanol (60 ml). The reaction mixture was warmed to reflux,maintained for 2 h, and was concentrated under reduce pressure. Theresidue was partitioned between ethyl acetate (250 mL) and saturatedsodium carbonate (50 mL) and the organic layer was washed with saturatedsodium carbonate (50 mL) and brine (50 mL). The organic layer was dried(sodium sulfate) and concentrated to provide 8.00 g (98%) of the esteras a liquid.

IsoamyInitrite (225 mL) was added to a solution of the ester (420 g,1.46 mol) in ethanol (3 L) in a 10 L three-necked round bottom flask andthe mixture was warmed to 60° C. A solution of sodium ethoxide, preparedfrom sodium metal (33.5 g, 1.46 mmol) in ethanol (1 L) was addeddropwise and the reaction mixture was maintained for 2 h. The reactionmixture was allowed to cool to rt and was neutralized with 2 Nhydrochloric acid. The reaction mixture was extracted with ethyl acetate(4×2 L) and the combined organic layers were washed with water (2×1 L)and brine (2×1 L) and dried (sodium sulfate). The residue was purifiedby chromatography (1/1 to 0/1 hexane/ethyl acetate) to provide 110 g ofthe product (28%).

10% Palladium on carbon (1.5 g) and triethylamine (7.5 g, 82.4 mmol)were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20g, 0.081 mol) in ethanol (300 ml) at 0° C. under an atmosphere ofnitrogen. The nitrogen atmosphere was removed by evacuation and replacedwith hydrogen gas, and the reaction mixture was maintained for 1 hour.The hydrogen atmosphere was removed by evacuation and replaced withnitrogen gas, and the palladium removed by filtration through Celite.The filter cake was washed with ethanol (3×50 mL) and the filtrates wereconcentrated. The residue was dissolved in dichloromethane (200 mL) andthe solution was washed with water (4×50 mL), dried (sodium sulfate) andevaporated to provide 13.0 g of the product as a yellow solid (96%). Theester was saponified using sodium hydroxide to provide the acid whichwas coupled with the bicyclobase according to procedure A.

-   Literature reference: Angell, R. M.; Baldwin, I. R.; Bamborough, P.;    Deboeck, N. M.; Longstaff, T.; Swanson, S. WO04010995A1

The following acid and esters were prepared using this method:

-   Ethyl 6-bromo-1,2-benzisoxazole-3-carboxylate.-   Ethyl 1,2-benzisoxazole-3-carboxylate.-   1,2-Benzisoxazole-3-carboxylic acid.

Procedure 17:

Procedure 17 provides a method for the preparation of5-difluoromethoxyindazole-3-acid from 3-bromo-4-nitrophenol.

3-Bromo-4-nitrophenol (10.0 mmol) was added to a suspension of sodiumhydroxide (29.0 mmol) in N,N-dimethylformamide (15 mL) and thesuspension was maintained for 15 min at rt. The reaction mixture wascooled to 0° C. and was treated with ethyl chlorodifluoroacetate (20.0mmol). The reaction mixture was heated at 70° C. for 16 h and wasconcentrated. The residue was diluted with ice water (200 mL) and wasextracted with ethyl acetate (3×100 mL). The combined organic layerswere dried (magnesium sulfate) and concentrated to provide thedifluoromethyl ether in 75% yield as a yellow oil.

Diethyl malonate (328 mmol) was added dropwise to a suspension of sodiumhydride (328 mmol) in dimethylsulfoxide (40 mL) at 0° C. The reactionmixture was warmed to 60° C. and maintained for 0.5 h. A solution of thedifluoromethyl ether (149 mmol) in dimethylsulfoxide (80 mL) was addeddropwise and the reaction mixture was heated at 100° C. for 5 h. Thecooled solution was poured onto ice water, and the aqueous layer wasextracted with dichloromethane (3×100 mL). The combined organic layerswere dried (magnesium sulfate) and concentrated to give the crudediester in 112% yield as an oil. The diester (167 mmol), sodiumhydroxide (500 mmol), and water (335 mL) were combined and heated at 60°C. for 1 h. The reaction mixture was allowed to cool to rt and theaqueous layer was washed with dichloromethane (3×100 mL). The pH of theaqueous layer was cautiously adjusted to 1 with concentratedhydrochloric acid and the reaction mixture was heated at 60° C. for 1 h.The suspension was cooled to 5° C. and the solids were collected byfiltration and dried to provide the acid in 61% yield.

Acetyl chloride (203 mmol) was added dropwise to ethanol (300 mL) at 0°C. After 0.5 h, the acid (101 mmol) was added and the reaction mixturewas heated at reflux for 15 h. The reaction mixture was concentrated andthe residue was partitioned between dichloromethane (200 mL) andsaturated sodium bicarbonate (100 mL). The aqueous layer was furtherextracted with dichloromethane (2×200 mL) and the combined organiclayers were dried (magnesium sulfate) and concentrated to provide theester in 60% yield as a brown oil.

The ester (60.4 mmol) was dissolved in ethanol (103 mL), diluted withwater (71 mL), and was treated with ammonium chloride (243 mmol) andiron powder (301 mmol). The reaction mixture was heated at reflux for 10minutes and the suspension was filtrated through Celite and the filtercake was washed with ethanol three times. The filtrate was concentrated,the residue was suspended in 2 N hydrochloric acid and was stirredvigorously for 0.5 h. The aqueous layer was washed with ethyl acetate(3×50 mL) and the pH adjusted to 9-10 with 5 M sodium hydroxide. Theaqueous layer was extracted with chloroform (3×100 mL) and the combinedorganic layers were dried (magnesium sulfate). Acetic anhydride (392mmol), isoamyl nitrite (291 mmol), and potassium acetate (51.0 mmol)were added to the organic layer and the suspension was heated at refluxfor 16 h. The solution was evaporated and the residue was partitionedbetween saturated sodium bicarbonate (50 mL) and dichloromethane (100mL). The aqueous layer was further extracted with dichloromethane (2×100mL) and the combined organic layers were dried (magnesium sulfate) andconcentrated to provide the N-acetylindazole ester in 79% yield as abrown oil.

The ester (63.8 mmol), sodium hydroxide (193 mmol), and water (65 mL)were combined and the reaction was maintained for 24 h at 60° C. Aftercooling to rt, the aqueous layer was washed with dichloromethane (3×50mL). The aqueous layer was adjusted to pH 1 with concentratedhydrochloric acid. The precipitated solids were collected by filtration,washed with water and dichloromethane, and dried to provide the acid in27% yield.

The following acids were prepared according to this method:

-   5-(Difluoromethoxy)-1H-indazole-3-carboxylic acid.

Procedure 18:

Procedure 18 provides a method for the preparation of6-difluoromethoxyindazole-3-acid from 4-nitrophenol.

4-Nitrophenol (162 mmol) was added to a suspension of sodium hydroxide(485 mmol) in N,N-dimethylformamide (150 mL) and the suspension wasmaintained for 15 min at rt. The reaction mixture was cooled to 0° C.and was treated with ethyl chlorodifluoroacetate (329 mmol). Thereaction mixture was heated at 70° C. for 16 h and was concentrated. Theresidue was diluted with ice water (200 mL) and was extracted with ethylacetate (3×100 mL). The combined organic layers were dried (magnesiumsulfate) and concentrated to provide the difluoromethyl ether in 59%yield as a yellow oil.

The nitro ether (149 mmol) was dissolved in ethanol (37.5 mL), dilutedwith water (25 mL), and was treated with ammonium chloride (84.7 mmol)and iron powder (105 mmol). The reaction mixture was heated at refluxfor 30 minutes and the suspension was filtered through Celite. Thefilter cake was washed with ethanol three times and the combinedfiltrates were concentrated. The residue was dissolved in water and thepH adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer wasextracted with ethyl acetate (3×100 mL) and the combined organic layerswere dried (magnesium sulfate) and concentrated to a yellow oil. The oilwas dissolved in acetic anhydride (23.5 mmol) and the reaction mixturewas maintained at rt for 16 h. The reaction mixture was diluted withwater (50 mL) and was neutralized with solid sodium bicarbonate. Theprecipitated solids were isolated by filtration, washed with water, anddried to provide the acetamide in 62% yield as a light yellow solid.

Acetic anhydride (19.6 mmol) was added to a solution of the acetamide(13.2 mmol) in chloroform (20 mL) and the reaction mixture was warmed toreflux. Fuming nitric acid (16.0 mmol) was added dropwise and thereaction mixture was maintained at reflux for 30 min. The cooledsolution was diluted with water (20 mL) and the aqueous layer wasextracted with dichloromethane (3×10 mL). The combined organic layerswere dried (magnesium sulfate) and concentrated to provide thenitro-amide in 83% yield.

The amide (11.0 mmol), sodium hydroxide (43.8 mmol), and water (10 mL)were combined and the reaction mixture was maintained for 1.5 hour at60° C. the reaction was allowed to cool to rt and the precipitatedsolids were isolated by filtration, and washed with water, and dried toprovide the aniline in 98% yield as a light yellow solid.

The aniline (15.7 mmol) was mixed with 40% hydrobromic acid (14.3 g) andwater (10 mL) and the reaction mixture was warmed to 80-90° C. in orderto completely dissolve the aniline. The reaction mixture was cooled to0° C. and a solution of sodium nitrite (23.2 mmol) in water (5.3 mL) wasadded during a 15 min period. The solution was maintained for 40 minutesat 0-5° C. and filtered. Copper (I) bromide (18.8 mmol) was dissolved in40% hydrobromic acid (21 mL) and was cooled to 0° C. The solution of thediazo salt was added slowly to the copper solution and the mixture wasmaintained for 30 min at 0-10° C. The reaction mixture was heated at 60°C. for 30 min and then at 100° C. for 10 min to ensure completion. Thereaction mixture was allowed to cool to rt and was extracted withdichloromethane (3×40 mL). The combined organic layers were washed with1 M sodium hydroxide, water, 1 N hydrochloric acid, and water. Theorganic layer was dried (magnesium sulfate) and concentrated to providethe nitro bromide in 76% yield as a light yellow solid.

Diethyl malonate (25.7 mmol) was added dropwise to a suspension ofsodium hydride (25.8 mmol) in dimethylsulfoxide (5 mL) at 0° C. Thereaction mixture was warmed to 60° C. and maintained for 30 min. Asolution of the nitro bromide (11.7 mmol) in dimethylsulfoxide (7 mL)was added dropwise and the reaction mixture was heated at 100° C. for 5h. The cooled solution was poured onto ice water and the aqueous layerwas extracted with dichloromethane (3×100 mL). The combined organiclayers were dried (magnesium sulfate) and concentrated to give the crudediester as an oil. The diester (11.7 mmol), sodium hydroxide (35 mmol),and water (20 mL) were combined and heated at 60° C. for 1 h. Thereaction mixture was allowed to cool to rt and the aqueous layer waswashed with dichloromethane (3×100 mL). The pH of the aqueous layer wascautiously adjusted to 1 with concentrated hydrochloric acid and thereaction mixture was heated at 60° C. for 1 h. The suspension was cooledto 0° C. and the solids were collected by filtration and dried toprovide the acid in 64% yield.

Acetyl chloride (15.3 mmol) was added dropwise to ethanol (50 mL) at 0°C. After 30 min, the acid (7.69 mmol) was added and the reaction mixturewas heated at reflux for 15 h. The reaction mixture was concentrated andthe residue was partitioned between dichloromethane (20 mL) andsaturated sodium bicarbonate (10 mL). The aqueous layer was furtherextracted with dichloromethane (2×20 mL) and the combined organic layerswere dried (magnesium sulfate) and concentrated to provide the ester in94% yield as a brown oil.

Acetic anhydride (6.0 mL) was added to a suspension of the ester (3.64mmol), and acetic acid (7.0 mL) at 0° C. Zinc dust (14.6 mmol) was addedin portions over 15 min and the reaction mixture was maintained for 30min at 0° C. and then for 1.5 h at rt. Additional zinc powder (6.15mmol) was added and the reaction maintained for 3 h. The suspension wasfiltered through Celite and the filtrate was concentrated. The residuewas partitioned between saturated sodium bicarbonate (10 mL) and ethylacetate (20 mL). The aqueous layer was further extracted with ethylacetate (3×20 mL) and the combined organic layers were dried (magnesiumsulfate) and concentrated to provide the acetamide in 92% yield as abrown oil.

Acetic anhydride (13.7 mmol), isoamyl nitrite (13.7 mmol), and potassiumacetate (2.04 mmol) were added to a solution of the acetamide (3.92mmol) in chloroform (20 mL) and the suspension was heated at reflux for16 h. The solution was evaporated and the residue was partitionedbetween saturated sodium bicarbonate (10 mL) and dichloromethane (20mL). The aqueous layer was further extracted with dichloromethane (2×20mL) and the combined organic layers were dried (magnesium sulfate) andconcentrated to provide the crude N-acetylindazole ester as a brown oil.

The ester (3.36 mmol), sodium hydroxide (10 mmol) and water (5 mL) werecombined and the reaction was maintained for 24 h at 60° C. Aftercooling to rt, the aqueous layer was washed with dichloromethane (3×30mL). The aqueous layer was adjusted to pH 1 with concentratedhydrochloric acid and the precipitated solids were collected byfiltration, washed with water and dichloromethane, and dried to providethe acid in 26% yield.

The following acids were prepared according to this method:

-   6-(Difluoromethoxy)-1H-indazole-3-carboxylic acid.

Procedure 19:

Procedure 19 provides a method for the coupling between brominatedbenzisothiazole-3-carboxylic esters and brominated indazole-3-carboxylicesters and Grignard reagents to form alkyl- and heterocycle-substitutedacids.

A 0.5 M solution of Grignard reagent (25.0 mmol, 3.7 eq) intetrahydrofuran was diluted with tetrahydrofuran (60 mL) and treatedwith a 0.5 M solution of zinc chloride (25.0 mmol, 3.7 eq) intetrahydrofuran at rt. After 10 min, the brominated ester (0.30 mmol)and bis(triphenylphosphine)palladium (II) chloride (0.95 mmol, 0.1 eq)were added to the suspension. The reaction mixture was maintained for 1h at ambient temperature then at 65° C. for 1 h. The reaction wasquenched with saturated ammonium chloride and was extracted withdichloromethane (3×). The extracts were dried over sodium sulfate andconcentrated to dryness. The residue was purified by chromatographyusing a gradient of 100/0 to 90/10 dichloromethane/methanol to providethe alkyl- or aryl-substituted amide. The amide was dissolved in amixture of methanol/tetrahydrofuran/water (90/10/20 mL) and was treatedwith sodium hydroxide (5.8 g). The mixture was heated at reflux for 12h, cooled to rt, filtered, and was acidified to pH<2 by the slowaddition of conc. hydrochloric acid. The aqueous layer was extractedwith ethyl acetate (2×) and was dried over sodium sulfate. Concentrationof the extracts gave the acid in 38% yield. The acid was coupled to thebicyclobases according to procedure A.

This procedure was used, with slight modifications, to derivatizebrominated indazole-3-piperidine carboxamides with various Grignardreagents. The Grignard reagent of thiazole is commercially available.Alternatively, the aryllithium and the corresponding arylzinc reagentcan be generated according to the procedure outlined by Reeder, M. R.;et. al. Org. Proc. Res. Devel. 2003, 7, 696. The zinc reagents ofoxazole, 4-methylthiazole, and 5-methylthiazole were prepared accordingto this procedure.

The following acids were prepared using this method:

-   6-(1,3-Thiazol-2-yl)-1H-indazole-3-carboxylic acid.-   5-(1,3-Thiazol-2-yl)-1H-indazole-3-carboxylic acid.-   5-(4-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic acid.-   5-(5-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic acid.-   6-(4-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic acid.-   6-(5-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic acid.-   5-(1,3-Oxazol-2-yl)-1H-indazole-3-carboxylic acid.-   6-(1,3-Oxazol-2-yl)-1H-indazole-3-carboxylic acid.

Procedure 20:

Procedure 20 provides a method for the preparation of alkoxy indazoleacids from the corresponding benzyloxy indazole esters using alkylationconditions.

A solution of ethyl 5-(benzyloxy)-1H-indazole-3-carboxylate (2.70 mmol)in tetrahydrofuran (10 mL) was added dropwise to a 0° C. suspension ofsodium hydride (60% mineral oil dispersion, 8.1 mmol) in tetrahydrofuran(54.0 mL). The reaction was maintained at 0° C. for 1 h.[β-(Trimethylsilyl)ethoxy]methyl chloride (3.2 mmol) was added and thereaction mixture was maintained for 1 h. The reaction was partitionedbetween water (50 mL) and ethyl acetate (50 mL) and the organic layerwas washed with brine (25 mL), dried (magnesium sulfate), andconcentrated. The residue was purified by chromatography (95/5 to 85/15hexanes/ethyl acetate to provide the protected indazole in 89% yield.

Ethyl5-(benzyloxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylate(9.38 mmol) was added to a suspension of 10% palladium on carbon (249mg) in ethanol (66.7 mL). The reaction was shaken under an atmosphere ofhydrogen (50 psi) for 4.0 h. The reaction was filtered through Celiteand concentrated to give the phenol in 87% yield as a white solid.

Cyclopropylmethyl bromide (1.19 mmol) and potassium carbonate (2.38mmol) was added to a solution of5-hydroxy-1-(2-trimethylsilanylethoxymethyl)-1H-indazole-3-carboxylicacid ethyl ester (5.94 mmol) in acetonitrile (10.0 mL) The suspensionwas heated at 60° C. for 4.0 h. The reaction was partitioned betweenwater (50 mL) and ethyl acetate (50 mL) and the organic layer was washedwith brine (25 mL), dried (magnesium sulfate), and concentrated. Theresidue was purified by chromatography (100/0 to 85/15 hexanes/ethylacetate) to yield the purified ethyl ester. The ester was dissolved inethanol (10 mL) and 5 N sodium hydroxide (3 mL) was added. The mixturewas allowed to stand overnight and was diluted with water (20 mL) andacidified to pH 1 with 3 N hydrochloric acid. The solid was collected byvacuum filtration to give the acid in 72% yield as a white solid.

The following acids were prepared using this method:

-   5-(Cyclopropylmethoxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic    acid.-   6-(Cyclopropylmethoxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic    acid.-   5-(Cyclopentyloxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic    acid.-   6-(Cyclopentyloxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic    acid.-   5-(2,2,2-Trifluoroethoxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic    acid.-   6-(2,2,2-Trifluoroethoxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic    acid.

Procedure 21:

Procedure 21 provides a method for the preparation of alkoxy indazoleacids from the corresponding benzyloxy indazole esters using Mitsunobuconditions.

Diisopropyl azodicarboxylate (0.618 mmol) was added dropwise to asolution of ethyl5-hydroxy-1-(2-trimethylsilanylethoxymethyl)-1H-indazole-3-carboxylate(0.594 mmol), 1-methyl-3-pyrrolidinol (0.594 mmol), andtriphenylphosphine (0.594 mmol) in tetrahydrofuran (3.6 mL). Thereaction was maintained for 16 h and was concentrated. The residue waspurified by chromatography (100/0 to 90/10 ethyl acetate/[70/30/2 ethylacetate/methanol/dimethylethylamine] to provide the ether product in 49%yield. The ester was saponified to provide the acid which was coupled tothe bicyclobase using Procedure C.

The following acids were prepared using this method:

-   5-[(1-Methylpyrrolidin-3-yl)oxy]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-3-carboxylic    acid.-   5-[(1-Benzylpyrrolidin-3-yl)oxy]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-3-carboxylic    acid.-   5-[2-(Dimethylamino)ethoxy]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic    acid.-   5-(2-Pyrrolidin-1-ylethoxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic    acid.-   5-(2,3-Dihydro-1H-inden-2-yloxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic    acid.-   5-(Tetrahydro-2H-pyran-4-yloxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic    acid.

Procedure 22:

Procedure 22 provides a method for the preparation of1-(3-thienyl)-1H-indazole-3-carboxylic acid from the correspondingindazole ester.

Ethyl 1H-indazole-3-carboxylate (5.50 mmol), 3-thienylboronic acid (7.50mmol), copper (II) acetate (5.01 mmol), triethylamine (24.7 mmol), andpyridine (40.4 mmol) were dissolved in 1,4-dioxane (39.8 mL). Thereaction was maintained at rt for 16 h and was diluted with water (50mL) and ethyl acetate (50 mL). The reaction mixture was filtered throughCelite and the organic layer was washed with brine (25 mL), dried(magnesium sulfate), and concentrated. The residue was purified bychromatography (90/10 to 70/30 hexanes/ethyl acetate) to yield theN-arylindazole ester in 35% yield. The ester was saponified usingstandard conditions and the resultant acid was used in Procedure A.

Procedure 23:

Procedure 23 provides a method for the preparation of1,8-dihydropyrrolo[3,2-g]indazole-3-carboxylic acid from ethyl6-bromo-7-nitro-1H-indazole-3-carboxylate.

A 0.50 M solution of zinc chloride in tetrahydrofuran (11 ml) was addedto a 0.50 M solution of (1,3-dioxolan-2-ylmethyl)magnesium bromide intetrahydrofuran (11 mL) and the reaction mixture was maintained for 20min. An aliquot (5.5 mL) of the zinc reagent solution was added to eachof 4 microwave tubes containing ethyl6-bromo-7-nitro-1H-indazole-3-carboxylate (143 mmol) andbis(tri-t-butylphosphine)palladium(0) (26 mg, 0.051 mmol). The reactionwas heated in a microwave reactor at 160° C. for 10 min. The reactionwas partitioned between water (50 mL) and ethyl acetate (50 mL),filtered through Celite and the organic layer was washed with brine (25mL), dried (magnesium sulfate), and concentrated. The residue waspurified by chromatography (80/20 to 60/40 hexanes/ethyl acetate) toyield the dioxolane product in 46% yield.

Ethyl 6-(1,3-dioxolan-2-ylmethyl)-7-nitro-1H-indazole-3-carboxylate(0.657 mmol) was added to a suspension of 10% palladium on carbon (100mg) in ethanol (30 mL). The reaction mixture was shaken under anatmosphere of hydrogen gas for 4 h. The reaction mixture was filteredthrough Celite and concentrated to give the amine in 94% yield as anoil.

Ethyl 7-amino-6-(1,3-dioxolan-2-ylmethyl)-1H-indazole-3-carboxylate (0.371 mmol) was dissolved in tetrahydrofuran (30 mL) and treated with 6 Mhydrogen chloride (5 mL). The reaction mixture was maintained for 16 hand was partitioned between water (30 mL) and ethyl acetate (30 mL). Theorganic layer was washed with brine (25 mL), dried (magnesium sulfate),and concentrated. The residue was purified by chromatography (90/10 to70/30 hexanes/ethyl acetate) to yield the pyrrolidine in 72% yield.

Ethyl 1,8-dihydropyrrolo[3,2-g]indazole-3-carboxylate (0.266 mmol) wasdissolved in ethanol (2 mL) and 5.0 M of sodium hydroxide (1.00 mL) andthe reaction was maintained for 16 h. The reaction mixture wasneutralized with 3 N hydrochloric acid and was partitioned between water(30 mL) and ethyl acetate (30 mL). The layers were separated and theorganic layer was washed with brine (25 mL), dried (magnesium sulfate),and concentrated in vacuo to provide the acid in 41% yield. The acid wasused without further purification.

Procedure 24:

Procedure 24 provides a method for the preparation of alkoxypyrrolidinesubstituted indazole-3-carboxylic acids from the correspondingnitro-1H-indazole-3-carboxylates.

[β-(Trimethylsilyl)ethoxy]methyl chloride (10.2 mmol) was added dropwiseto a suspension of ethyl 5-nitro-1H-indazole-3-carboxylate (8.50 mmol)and N,N-diisopropylethylamine (25.5 mmol) in dichloromethane (20.0 mL).The heterogeneous reaction mixture was maintained at rt for 16 hwhereupon the reaction mixture gradually became homogeneous. Thereaction mixture was filtered through silica gel (ca. 40 g) andconcentrated. The residue was diluted with ethanol (50.0 mL) and 10%palladium on carbon (200 mg) was added under a flow of nitrogen gas. Thereaction was shaken under an atmosphere of hydrogen for 4 h and thereaction mixture was filtered through Celite and concentrated. Theresidue was purified by chromatography (70/30 to 50/50 hexanes/ethylacetate) to yield the aniline in 60% yield as a 2/1 mixture of 1- and2-SEM regioisomers.

Ethyl5-amino-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylate(3.61 mmol) was combined with 1,4-dibromo-2-butanol (3.80 mmol) andpotassium carbonate (3.47 mmol) in triethyl phosphate (10.0 mL) and thereaction was heated at 120° C. for 2 h. The reaction mixture was loadedonto a SCX column (3×10 g) and flushed with 5 volumes of methanol. Thepartially purified product was then eluted using 2.0 M ammonia inmethanol and the product fractions were combined and concentrated. Theresidue was purified by chromatography (90/10 to 70/30 hexanes/ethylacetate) to provide the pyrrolidine in 55% yield.

A solution of ethyl5-(3-hydroxypyrrolidin-1-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylate(0. 493 mmol) in tetrahydrofuran (20.0 mL) was cooled to −78° C. A 0.5 Msolution of potassium bis(trimethylsilyl)amide in toluene (1.18 mL) wasadded dropwise and the reaction mixture was maintained for 30 min.2,2,2-Trifluoroethyl nonafluorobutanesulfonate (0. 493 mmol) was addedand the reaction mixture was allowed to warm to room temperature and wasmaintained for 4 h. The reaction mixture was partitioned between water(50 mL) and ethyl acetate (50 mL) and the organic layer was washed withbrine (25 mL), dried (magnesium sulfate), and concentrated. The residuewas purified by chromatography (90/10 to 80/20 hexanes/ethyl acetate) toyield the alkoxypyrrolidine in 42% yield.

The ester (0. 172 mmol) was dissolved in ethanol (5.0 mL) by warmingslightly. A 5.0 M of sodium hydroxide (2.00 mL) was added and thereaction mixture was maintained overnight. The reaction mixture wasdiluted with water (50 mL), neutralized to pH 6-7 with 3.0 Nhydrochloric acid, and was extracted with ethyl acetate (2×25 mL). Theorganic layer was washed with brine (25 mL), dried (magnesium sulfate),and concentrated to provide the acid in 89% yield. The acid was usedwith no further purification.

The following acids were prepared by this method:

-   5-[3-(Hydroxy)pyrrolidin-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic    acid.-   5-[3-(Methoxy)pyrrolidin-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic    acid.-   5-[3-(Benzyloxy)pyrrolidin-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic    acid.-   5-[3-(2,2,2-Trifluoroethyl)pyrrolidin-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic    acid.

Procedure 25:

Procedure 25 provides a method for the preparation of aminomethylsubstituted indazole-3-carboxylic acids from the corresponding bromides.

A solution of di-tert-butyldicarbonate (188 mmol) in tetrahydrofuran (50mL) was cautiously added to a mixture of5-bromo-1H-indazole-3-carboxylic acid (62.2 mmol) and4-dimethylaminopyridine (19.0 mmol) in tert-butyl alcohol (150 mL) andtetrahydrofuran (150 mL) at 60° C. The mixture was maintained at 60° C.until gas evolution ceased (approx. 4 h). The reaction mixture wasallowed to cool to rt, diluted with ethyl acetate, washed with water,sodium bicarbonate, and brine, dried (sodium sulfate) and concentrated.The residue was dissolved in 1/1 hexanes/ethyl acetate (−300 mL) andfiltered through of silica gel (approx. 40 g). The silica was washedwith additional 1/1 hexanes/ethyl acetate (500 mL) and the combinedeluant was concentrated. The residue was dissolved in methanol (100 mL)and tetrahydrofuran (100 mL) and was treated with 2.0 M sodium hydroxide(100 mL). The reaction mixture was maintained for 2 h at rt and waspartitioned between water (200 mL) and ethyl acetate (200 mL). Theorganic layer was washed with brine (50 mL), dried (magnesium sulfate),and concentrated. The residue was triturated with hexanes to provide theester in 80% yield.

Into a 1-Neck round-bottom flask was added sodium hydride (60% mineraloil dispersion) (6.00 mmol) and tetrahydrofuran (90 mL) The reaction wascooled to −78° C. and a solution of tert-butyl5-bromo-1H-indazole-3-carboxylate (4.00 mmol) in tetrahydrofuran (10.0mL) was added. The reaction was heated at 25° C. and was maintained for30 min. The reaction was cooled to −78° C. and tert-butyllithium inpentane (1.7 M, 3.6 mL) was added dropwise. The reaction was maintainedat −78° C. for 15 minutes and N,N-dimethylformamide (20 mmol) was added.The reaction was maintained at −78° C. for 30 minutes, then quenchedwith methanol (0.5 mL) and allowed to warm to room temperature. Thereaction was partitioned between water (100 mL) and ethyl acetate (100mL) and the organic layer was washed with brine (25 mL), dried(magnesium sulfate), and concentrated. The residue was purified bychromatography (80/20 to 60/40 hexanes/ethyl acetate) to yield thebenzaldehyde in 52% yield.

Sodium triacetoxyborohydride (4.74 mmol) was added to a suspension oftert-butyl 5-formyl-1H-indazole-3-carboxylate (2.03 mmol) anddimethylamine hydrochloride (4.74 mmol) in 1,2-dichloroethane (50.0 mL).The reaction mixture was maintained for 3 days at rt. The reactionmixture was washed with water (50 mL) and brine (25 mL), dried(magnesium sulfate), and concentrated. The residue was loaded onto a SCXcolumn (10 g) and washed with 5 volumes of methanol. The purifiedproduct was then eluted using 2.0 M ammonia in methanol to provide theamine in 86% yield

tert-Butyl 5-[(dimethylamino)methyl]-1H-indazole-3-carboxylate (1.74mmol) was dissolved in trifluoroacetic acid (3.00 mL) and the reactionmixture was maintained for 16 h. The reaction mixture was concentratedand was loaded onto a SCX column (10 g) and flushed with 5 volumes ofmethanol. The purified product was then eluted using 2.0 M ammonia inmethanol to provide the acid in 90% yield.

The following compounds were prepared using this method:

-   5-[(Dimethylamino)methyl]-1H-indazole-3-carboxylic acid.-   5-[(Diethylamino)methyl]-1H-indazole-3-carboxylic acid.-   5-[(Pyrrolidin-1-yl)methyl]-1H-indazole-3-carboxylic acid.-   tert-Butyl 5-bromo-1H-indazole-3-carboxylate.

Procedure 26:

Procedure 26 provides a method for the preparation of 4-methoxyindazoleacid from 4-methoxyaniline.

A solution of 4-methoxyaniline (1.63 mol) in acetic acid (244 mL) wastreated with acetic anhydride (244 mL) and zinc powder (30.8 mmol) andthe reaction mixture was heated at reflux for 30 min. The suspension wasallowed to cool to rt and was filtered and concentrated. The residue wasdiluted with water (200 mL) and the pH of the solution was adjusted to 8with 10% sodium hydroxide. The precipitated solids were collected byfiltration, washed with water (1 L), and dried to give the acetamide in94% yield as a purple solid.

Concentrated nitric acid (210 mL) was added dropwise to a solution ofthe acetamide (1.52 mol) in dichloromethane (1.5 L) at rt. The reactionmixture was heated at reflux for 1 h and was allowed to cool to rt. Thereaction mixture was washed with water (1.0 L), saturated sodiumcarbonate (1.0 L), and water (1.0 L). The organic layer was dried overanhydrous sodium sulfate and concentrated to provide the nitroacetamidein 83% yield as an orange solid.

A solution of the nitroacetamide (1.27 mol) in water (1.27 L) wastreated with sodium hydroxide (5.07 mol) and the reaction mixture washeated at 60° C. for 2 h. The precipitated solids were collected byfiltration, washed with water, and dried to provide the nitroaniline in85% yield as an orange solid.

A solution of sodium nitrite (1.48 mol) in water (250 mL) was added to acold (0-5° C.) solution of the nitroaniline (1.08 mol) in hydrobromicacid (4.87 mol) (prepared by heating the reaction mixture at 90° C. for2 h). The reaction mixture was maintained for 40 min and was filtered.The filtrate was added dropwise to a cold (0-5° C.) solution of copper(I) bromide (1.81 mol) in hydrobromic acid (640 mL) and the reactionmixture was maintained for 30 min. The reaction mixture was warmed to60° C. and was maintained for 30 min. The reaction mixture was warmed toreflux and was maintained for 1 h. The reaction mixture was diluted withwater (2 L) and was extracted with dichloromethane (3×1 L). The combinedorganic layers were washed with 10% sodium hydroxide (1.0 L), water (2.0L), 10% hydrochloric acid (1.6 L) and water (2.0 L), dried (magnesiumsulfate) and concentrated. The residue was recrystallized from ethanolto provide the bromide in 50% yield as a yellow solid.

Iron powder (1.08 mol) and ammonium chloride (862 mmol) were added to asolution of the bromide (216 mmol) in ethanol (200 mL) and water (140mL) and the reaction mixture was heated at reflux for 1 h. Thesuspension was filtered and concentrated and the residue was extractedwith ethyl acetate (3×200 mL). The combined organic layers were dried(sodium sulfate) and concentrated to give the bromoaniline in 96% yieldas a yellow liquid.

A solution of the bromoaniline (208 mmol) in 50% hydrochloric acid (40mL) was added to a solution of trichloroacetaldehyde hydrate (312 mmol)and sodium sulfate (967 mmol) in water (450 mL) and the reaction mixturewas maintained for 1 h. A solution of hydroxylamine hydrochloride (793mmol) in water (240 mL) was added and the reaction mixture was heated at60° C. for 2 h. The aqueous layer was decanted and the residual red oil,which solidifies upon standing, was purified by chromatography (6/6/1petroleum ether/dichloromethane/ethyl acetate) to provide the α-oximeamide in 29% yield as a light yellow solid.

The α-oxime amide (58.6 mmol) was added in one portion to warm (40° C.)90% sulfuric acid (16 mL) and the reaction mixture was heated at 60° C.for 30 min. The reaction mixture was allowed to cool to rt and waspoured into ice water. The precipitated orange solids were collected byfiltration and dried. The crude product was purified by chromatography(15/1 petroleum ether/ethyl acetate) to provide the isatin in 57% yieldas a yellow solid.

The isatin (20.7 mmol) was mixed with 1 M sodium hydroxide (23 mL) andthe reaction mixture was heated to 30-40° C. for 30 min. The reactionmixture was cooled to 0° C. and treated with a solution of sodiumnitrite (20.7 mmol) in water (5.1 mL) and was maintained for 20 min.That solution was added dropwise to a cold (0-5° C.) solution ofconcentrated sulfuric acid (2.24 mL) in water (43.3 mL) and the reactionmixture was maintained for 0.5 h. A solution of tin (II) chloride (50.5mmol) in concentrated hydrochloric acid (19.6 mL) was added dropwise andthe reaction mixture was maintained at 0-5° C. for 1 h. The precipitatedsolids were isolated by filtration and dried to provide the indazoleacid as a yellow solid (100% by mass).

Acetylchloride (18 mL) was added to methanol (180 mL) at 0° C. and thereaction mixture maintained for 1 h. The indazole acid (21.8 mmol) wasadded and the reaction mixture was heated at reflux for 3 h. Thesolution was concentrated to dryness and the residue was suspended inwater and the pH adjusted to 7 with saturated sodium hydrogen carbonate.The mixture was extracted with ethyl acetate (3×100 mL), and thecombined organic layers were dried (magnesium sulfate) and concentrated.The crude product was purified by chromatography (2/1 petroleumether/ethyl acetate) to provide the indazole ester in 5% yield (twosteps) as a yellow solid.

The indazole ester (1.02 mmol) was combined with 10% palladium on carbon(30 mg) and methanol (20 mL) under an atmosphere of hydrogen gas for 30min at rt. The catalyst was removed by filtration and the eluent wasconcentrated to afford the de-brominated indazole ester in 24% yield asan orange solid.

1 M Sodium hydroxide (1.5 mL) was added to a solution of thede-brominated indazole ester (0.243 mmol) in methanol (3.0 mL) and thereaction mixture was heated at 60° C. for 3 h. The solution wasconcentrated, the pH adjusted to 1-2, and the solids collected byfiltration to provide the indazole acid in 100% yield as a yellow solid.

Procedure 27:

Procedure 27 provides a method for the preparation ofbenzyloxy-substituted indazole-3-carboxylic acids and esters from thecorresponding bromides.

Acetic anhydride (34 mL) and zinc dust (4.59 mmol) were added to asolution of 4-methoxynitrobenzene (230 mmol) in glacial acetic acid (34mL) and the reaction mixture was heated at reflux for 0.5 h. Thereaction mixture was poured into water (340 mL) and the pH of thesolution was adjusted to 8 with 10% sodium hydroxide. The precipitatedsolids were isolated by filtration, washed with water (100 mL), anddried to provide the acetamide in 88% yield.

65% Nitric acid (22 mL) was added dropwise over 0.5 h to a solution ofthe acetamide (200 mmol) in dichloromethane (200 mL). The reactionmixture was maintained for 1 h at rt and was heated at reflux for 1 h.The reaction mixture was washed with water (200 mL), saturated sodiumcarbonate solution (100 mL), and water (200 mL). The combined organiclayers were dried (magnesium sulfate) and concentrated to provide thenitro acetamide in 90% as a yellow solid.

The nitroacetamide (180 mmol) was added to 4 M sodium hydroxide (180 mL)and the reaction mixture was maintained for 2 h at 60° C. Theprecipitated solids were isolated by filtration, washed with water, anddried to provide the nitroaniline in 70% yield as a red solid.

A solution of sodium nitrite (11.8 g) in water (28 mL) was addeddropwise over 0.5 h to a solution of the nitroaniline (125 mmol) in 40%.hydrobromic acid (110 g) at 10° C. The reaction mixture was maintainedfor 40 min at 0-10° C. and was filtered. The filtrate was added dropwiseover 1 h to a 0° C., purple solution of copper (I) bromide (209 mmol) inhydrobromic acid (74 mL). The reaction mixture was allowed to warm toand maintained at rt for 30 min, was maintained at 60° C. for 0.5 h, andwas heated at reflux for 1 h. The reaction mixture was partitionedbetween water (2.0 L) and dichloromethane (600 mL) and the aqueous layerwas further extracted with dichloromethane (300 mL). The combinedorganic layers were washed with 10% sodium hydroxide (200 mL), water(600 mL), 10% hydrochloric acid (300 mL), and water (600 mL), dried(magnesium sulfate) and concentrated to provide the nitrobromide in 83%yield as a yellow oil.

A solution of boron tribromide (250 mmol) in dichloromethane (200 mL)was added drop wise over 1 h to a solution of the nitrobromide (100mmol) in dichloromethane (250 mL) at −78° C. The reaction mixture wasallowed to warm to rt and was maintained for 30 h.

The reaction mixture was cooled to 0° C., quenched with water (300 mL)and the aqueous layer was extracted with ethyl acetate (2×300 mL). Thecombined organic layers were washed with saturated sodium bicarbonate(2×300 mL), dried (magnesium sulfate), and concentrated to provide thenitrophenol in 87% yield as a brown crystalline solid.

Benzyl bromide (131 mmol) and potassium carbonate (130 mmol) were addedto a solution of the nitrophenol (87.0 mmol) in 2/1 acetonitrile/acetone(840 mL). The reaction mixture was heated at reflux for 17 h and wasconcentrated to dryness. The residue was suspended in ethyl acetate (756mL), filtered, and the organic layer was washed with water (567 mL), 1 Mhydrochloric acid (2×567 mL), and brine (567 mL). The organic layer wasdried (magnesium sulfate) and concentrated to the benzyl ether in 78%yield.

Diethyl malonate (890 mmol) was added drop wise over 1 h to a suspensionof sodium hydride (520 mmol) in dimethylsulfoxide (100 mL) at 0° C. Thebenzyl ether (44.0 mmol) was added and the reaction mixture was heatedat 100° C. for 5 h. The reaction mixture was poured into ice water andwas extracted with ethyl acetate (3×70 mL). The combined organic layerswere dried (magnesium sulfate) and concentrated to provide thediethylmalonate addition product. The diethylmalonate addition productwas diluted with a 4 M solution of sodium hydroxide (100 mL) and thereaction mixture was heated at 60° C. for 6 h. The solution wasextracted with dichloromethane (3×50 mL) and the aqueous layer wasadjusted to pH 1 with concentrated hydrochloric acid. The reactionmixture was heated at 60° C. for 1 h, allowed to cool to rt, and wasextracted with ethyl acetate (3×50 mL). The combined organic layers weredried (magnesium sulfate) and concentrated to provide the phenylaceticacid in 78% yield as a solid.

The phenylacetic acid (350 mmol) was added to a freshly preparedsolution of ethanolic hydrochloric acid [acetyl chloride (5 mL) wasadded to ethanol (100 mL)] and the reaction mixture was heated at refluxfor 20 h. The reaction mixture was concentrated to dryness and theresidue was partitioned between saturated sodium bicarbonate (200 mL)and ethyl acetate (150 mL). The aqueous layer was extracted with ethylacetate (2×50 mL) and the combined organic layers were dried (magnesiumsulfate), filtered and concentrated to provide the ester in 77% yield.

The nitro ester (27.0 mmol) was dissolved in acetic acid (60 mL) andacetic anhydride (44 mL) and was cooled to 0° C. Zinc dust (153 mmol)was added and the reaction mixture was allowed to warm to rt and wasmaintained for 2 h. Additional quantities of zinc dust (2×45.9 mmol)were added during a 3 h course of time. After 1 h, the reaction mixturewas filtered and the filter cake was washed with ethanol (100 mL). Thecombined filtrates were concentrated and the residue was partitionedbetween saturated sodium bicarbonate and ethyl acetate (50 mL). Thesolution was extracted with ethyl acetate (2×50 mL) and the combinedorganic layers were dried (magnesium sulfate), filtered and concentratedto provide the acetamide in 82% yield.

Isoamyl nitrite (47.2 g) was added dropwise over 30 min to a solution ofthe acetamide (21.0 mmol) in chloroform (80 mL) and acetic anhydride (45mL). Solid potassium acetate (7.13 mmol) was added in several portionsand the reaction mixture was heated at reflux for 1.5 h. The reactionmixture was washed with water (2×80 mL) and brine (80 mL), dried(magnesium sulfate), and concentrated to provide the acetylated indazoleester in 68% yield.

The acetylated indazole ester (15.0 mmol) was suspended in 2 M sodiumhydroxide (35 mL) and the reaction mixture was heated at 60° C. for 24h. The pH of the solution was adjusted to 1-2 with concentratedhydrochloric acid and the solids were collected by filtration and driedto provide 6-benzyloxy-1H-indazole-3-carboxylic acid in 28% yield as ayellow solid.

6-Benzyloxy-1H-indazole-3-carboxylic acid (1.85 mmol) was added to afreshly prepared solution of ethanolic hydrochloric acid [prepared fromethanol (20 mL) and acetyl chloride (5 mL)] and the reaction mixture washeated at reflux for 25 h and was concentrated. The residue waspartitioned between saturated sodium bicarbonate (20 mL) and ethylacetate (20 mL) and the layers were separated. The aqueous layer wasextracted with ethyl acetate (2×20 mL) and the combined organic layerswere dried (magnesium sulfate) and concentrated. The residue waspurified by chromatography (300/1 dichloromethane/methanol) to providethe product in 36.4% yield. Alternatively, the ester can be obtainedfrom the acetylated indazole ester by maintaining the acetylatedmaterial in 2 M ammonia in methanol for 30 min.

The following acids were prepared using this method:

-   6-Benzyloxy-1H-indazole-3-carboxylic acid.-   5-Benzyloxy-1H-indazole-3-carboxylic acid (from    4-benzyloxy-2-bromonitrobenzene: Parker, K. A.; Mindt, T. L. Org.    Lett. 2002, 4, 4265.).-   Ethyl 6-benzyloxy-1H-indazole-3-carboxylate.-   Ethyl 5-benzyloxy-1H-indazole-3-carboxylate.

Base Preparations.

The following procedures (28-29) detail the preparation of thebicyclobases that were not commercially available.

Procedure 28:

Procedure 28 provides a method for the preparation of N-alkylated3-aminoquinuclidines from 3-aminoquinuclidine.

Cyclopropanecarbonyl chloride (12 mmol) was added dropwise to a solutionof (R)-3-aminoquinuclidine (10 mmol) and N,N-diisopropylethylamine (30mmol) in dichloromethane (100 mL). The resulting solution was maintainedat rt for 4 h and was evaporated to dryness. The crude amide wasdissolved in tetrahydrofuran (150 mL) and was treated with lithiumaluminum hydride (66 mmol) in small portions. The reaction mixture wasquenched with sodium sulfate decahydrate and the resulting slurry wasdiluted with tetrahydrofuran and filtered through Celite. The filtratewas concentrated and the residue was then diluted with freshly preparedmethanolic hydrogen chloride (generated by the dropwise addition of 3 mLof acetyl chloride into 30 mL of methanol) and maintained at rt for 15min. The residue obtained by the removal of the volatiles wasrecrystallized (2-propanol/methanol) to provide the secondary amine in41% yield as a colorless solid.

The following bases were prepared using this method:

-   (3R)—N-(Cyclopropylmethyl)quinuclidin-3-amine dihydrochloride.-   (3S)—N-(Cyclopropylmethyl)quinuclidin-3-amine dihydrochloride.-   (3R)—N-(Methyl)quinuclidin-3-amine dihydrochloride.-   (3S)—N-(Methyl)quinuclidin-3-amine dihydrochloride.-   (3R)—N-(Ethyl)quinuclidin-3-amine dihydrochloride.-   (3S)—N-(Ethyl)quinuclidin-3-amine dihydrochloride.

Procedure 29:

Procedure 29 provides a method for the preparation of1-(1-azabicyclo[2.2.2]oct-3-yl)methanamine dihydrochloride fromquinuclidinone.

A solution of p-tolylsulfonylmethyl isocyanide (50 mmol) in ethanol (4mL) was added to a suspension of quinuclidone (40 mmol) in ethyleneglycol dimethyl ether (155 mL) at −5° C. Solid potassium tert-butoxide(130 mmol) was added in portions over 20 min. The Reaction mixture wasmaintained for 30 min at −5° C. and was then allowed to warm to the rtand maintained for an additional 3 h. The reaction mixture was filteredand was diluted with saturated hydrochloric acid in isopropanol. Thereaction mixture was filtered and diluted with ether. The resultingprecipitate was collected by filtration to provide the nitrile in 88%yield as a yellow solid.

The solution of the nitrile (35 mmol) in methanol (720 mL) was cooled to5° C. and was treated with concentrated hydrochloric acid (12 mL) and10% palladium on carbon (9.6 g). The reaction mixture was maintainedunder an atmosphere of hydrogen gas for 4.5 h at the rt. The catalystwas removed by filtration and the filtrate was concentrated to afford ayellow solid. The solid was dissolved in methanol and was diluted withethyl ether. The resulting precipitate was collected by filtration toprovide the nitrile in 32% yield as a yellow solid.

Representative Procedures.

The following procedures (A-AG) detail the preparation of thebicyclobase analogs.

Procedure A.

Procedure A provides a method for the coupling between3-aminoquinuclidine and carboxylic acids to form carboxamidederivatives.

To a solution of the carboxylic acid (16.1 mmol) inN,N-dimethylformamide (65 mL) was added HBTU (16.1 mmol), catalyticamount of dimethylaminopyridine, N,N-diisopropylethylamine (96.6 mmol)and 4 Å activated molecular sieves (2.6 g). The reaction mixture wasmaintained at room temperature for 2 h under nitrogen and then3-aminoquinuclidine dihydrochloride (16.1 mmol) was added. After 18 h,the solvent was removed under reduced pressure. The oily residue waspartitioned between saturated, aqueous sodium bicarbonate (25 mL) anddichloromethane (100 mL). The aqueous layer was further extracted with9/1 dichloromethane/methanol (5×100 mL) and the combined organic layerswere concentrated. The residue was purified by chromatography [90/10/1dichloromethane/methanol/ammonium hydroxide or 1/1 to 0/1 ethylacetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] or bypreparative HPLC, thus providing the product in 30%-70% yield.

The following compounds were prepared using this method:

Example 1N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 29% yield. ¹H NMR (CD₃OD) δ 8.52 (s, 1H),8.18 (s, 1H), 7.59 (d, J=8.9, 1H), 7.41 (dd, J=8.9, 1.9, 1H), 4.51 (m,1H), 3.80 (m, 1H), 3.44 (m, 5H), 2.36 (m, 1H), 2.24 (m, 1H), 2.09 (m,2H), 1.86 (m, 1H); LC/MS (EI) t_(R) 2.75, m/z 305 (M⁺+1).

Example 2N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 15% yield. LC/MS (EI) t_(R) 2.86, m/z 289(M⁺+1).

Example 3N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 30% yield. LC/MS (EI) t_(R) 2.76, m/z 305(M⁺+1).

Example 4N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 27% yield. LC/MS (EI) t_(R) 2.53, m/z 289(M⁺+1).

Example 5N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 32% yield. LC/MS (EI) t_(R) 5.15, m/z 355(M⁺+1).

Example 6N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 38% yield. LC/MS (EI) t_(R) 2.53, m/z 301(M⁺+1).

Example 7N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 27% yield. LC/MS (EI) t_(R) 5.13, m/z 355(M⁺+1).

Example 8N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 34% yield. LC/MS (EI) t_(R) 2.53, m/z 301(M⁺+1).

Example 9N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethyl)-1H-indazole-3-carboxamide

Prepared using Procedure A in 43% yield. LC/MS (EI) t_(R) 5.06, m/z 339(M⁺+1).

Example 10N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethyl)-1H-indazole-3-carboxamide

Prepared using Procedure A in 45% yield. LC/MS (EI) t_(R) 5.06, m/z 339(M⁺+1).

Example 11N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide

Prepared using Procedure A in 63% yield. LC/MS (EI) t_(R) 2.53, m/z 301(M⁺+1).

Example 12N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide

Prepared using Procedure A in 57% yield. LC/MS (EI) t_(R) 2.53, m/z 301(M⁺+1).

Example 13N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-fluoro-1H-indazole-3-carboxamide

Prepared using Procedure A in 62% yield. LC/MS (EI) t_(R) 2.53, m/z 289(M⁺+1).

Example 14N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-fluoro-1H-indazole-3-carboxamide

Prepared using Procedure A in 62% yield. LC/MS (EI) t_(R) 2.53, m/z 289(M⁺+1).

Example 15N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-methoxy-1H-indazole-3-carboxamide

Prepared using Procedure A in 14% yield. LC/MS (EI) t_(R) 2.50, m/z 301(M⁺+1).

Example 16N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamidehydroformate

Prepared using Procedure A in 20% yield. LC/MS (EI) t_(R) 3.09, m/z 272(M⁺+1).

Example 17N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamidehydroformate

Prepared using Procedure A in 20% yield. LC/MS (EI) t_(R) 3.12, m/z 272(M⁺+1).

Example 18N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure A in 30% yield. LC/MS (EI) t_(R) 3.40, m/z 355(M⁺+1).

Example 19N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1H-indazole-3-carboxamide

Prepared using Procedure A in 9% yield. LC/MS (EI) t_(R) 4.94, m/z 437(M⁺+1).

Example 20N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 24% yield. LC/MS (EI) t_(R) 3.62, m/z 353(M⁺+1).

Example 21N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 23% yield. LC/MS (EI) t_(R) 3.50, m/z 353(M⁺+1).

Example 22N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-methyl-1H-indazole-3-carboxamide

Prepared using Procedure A in 40% yield. LC/MS (EI) t_(R) 3.03, m/z 315(M⁺+1).

Example 23N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-ethyl-1H-indazole-3-carboxamide

Prepared using Procedure A in 63% yield. LC/MS (EI) t_(R) 3.26, m/z 329(M⁺+1).

Example 24N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-cyclopentyl-1H-indazole-3-carboxamide

Prepared using Procedure A in 87% yield. LC/MS (EI) t_(R) 5.45, m/z 369(M⁺+1).

Example 25N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-bromo-6-methoxy-1H-indazole-3-carboxamide

Prepared using Procedure A in 12% yield. LC/MS (EI) t_(R) 4.36, m/z379/381 (M⁺+1).

Example 26N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1,8-dihydropyrrolo[3,2-g]indazole-3-carboxamide

Prepared using Procedure A in 35% yield. LC/MS (EI) t_(R) 2.20, m/z 310(M⁺+1).

Example 27N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-benzyl-6-(difluoromethoxy)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 18% yield. LC/MS (EI) t_(R) 5.27, m/z 427(M⁺+1).

Example 28N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(3-thienyl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 16% yield. LC/MS (EI) t_(R) 5.10, m/z 353(M⁺+1).

Example 29N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(difluoromethoxy)-1H-indazole-3-carboxamide

Prepared using Procedure A in 30% yield. LC/MS (EI) t_(R) 4.41, m/z 337(M⁺+1).

Example 30N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(difluoromethoxy)-1H-indazole-3-carboxamide

Prepared using Procedure A in 16% yield. LC/MS (EI) t_(R) 4.27, m/z 337(M⁺+1).

Example 31N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 5.3% yield. LC/MS (EI) t_(R) 2.93, m/z 368(M⁺+1).

Example 32N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-methoxy-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 12% yield. LC/MS (EI) t_(R) 2.43, m/z 301(M⁺+1).

Example 33N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-6-methoxy-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 20% yield. LC/MS (EI) t_(R) 268.00, m/z319 (M⁺+1).

Example 34N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-fluoro-5-methoxy-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 29% yield. LC/MS (EI) t_(R) 2.40, m/z 319(M⁺+1).

Example 35N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy)-1H-indazole-3-carboxamide

Prepared using Procedure A in 34% yield. LC/MS (EI) t_(R) 3.71, m/z 337(M⁺+1).

Example 36N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy)-1H-indazole-3-carboxamide

Prepared using Procedure A in 22% yield. LC/MS (EI) t_(R) 3.72, m/z 337(M⁺+1).

Example 37N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 24% yield. LC/MS (EI) t_(R) 4.34, m/z 368(M⁺+1).

Example 38N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 21% yield. LC/MS (EI) t_(R) 4.50, m/z 368(M⁺+1).

Example 39N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyclopropyl-6-methoxy-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 10% yield. LC/MS (EI) t_(R) 4.66, m/z 341(M⁺+1).

Example 40N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-5-(3-thienyl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 13% yield. LC/MS (EI) t_(R) 5.10, m/z 383(M⁺+1).

Example 41N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-yl]-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 4% yield. LC/MS (EI) t_(R) 5.26, m/z 446(M⁺+1).

Example 42N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(methyloxy)pyrrolidin-1-yl]-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 46% yield. LC/MS (EI) t_(R) 2.39, m/z 370(M⁺+1).

Example 43N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(hydroxy)pyrrolidin-1-yl]-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 13% yield. LC/MS (EI) t_(R) 2.39, m/z 356(M⁺+1).

Example 44N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(1-methylpyrrolidin-3-yl)oxy]-1H-indazole-3-carboxamidedihydroformate

Prepared using Procedure A in 40% yield. LC/MS (EI) t_(R) 1.89, m/z 370(M⁺+1).

Example 45N-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 25% yield. LC/MS (EI) t_(R) 5.15, m/z 369(M⁺+1).

Example 46N-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-6-methoxy-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 25% yield. LC/MS (EI) t_(R) 2.80, m/z 315(M⁺+1).

Example 47N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclopropylmethoxy)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 37% yield. LC/MS (EI) t_(R) 4.66, m/z 341(M⁺+1).

Example 48N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclopentyloxy)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 30% yield. LC/MS (EI) t_(R) 4.90, m/z 355(M⁺+1).

Example 49N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2,2,2-trifluoroethoxy)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure Amod in 40% yield. LC/MS (EI) t_(R) 4.70, m/z369 (M⁺+1).

Example 50N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 36% yield. LC/MS (EI) t_(R) 4.59, m/z 341(M⁺+1).

Example 51N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2,2,2-trifluoroethoxy)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 78% yield. LC/MS (EI) t_(R) 4.75, m/z 369(M⁺+1).

Example 52N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(benzyloxy)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 33% yield. LC/MS (EI) t_(R) 5.09, m/z 377(M⁺+1).

Example 53N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yloxy)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 67% yield. LC/MS (EI) t_(R) 2.79, m/z 371(M⁺+1).

Example 54N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2,3-dihydro-1H-inden-2-yloxy)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 37% yield. LC/MS (EI) t_(R) 4.26, m/z 403(M⁺+1).

Example 55N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[2-(dimethylamino)ethoxy]-1H-indazole-3-carboxamidedihydroformate

Prepared using Procedure Amod in 24% yield. LC/MS (EI) t_(R) 1.90, m/z358 (M⁺+1).

Example 56N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-pyrrolidin-1-ylethoxy)-1H-indazole-3-carboxamidedihydroformate

Prepared using Procedure A in 49% yield. LC/MS (EI) t_(R) 1.88, m/z 384(M⁺+1).

Example 57N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-N-methyl-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure A in 12% yield. LC/MS (EI) t_(R) 2.52, m/z 315(M⁺+1).

Procedure B.

Procedure B provides a method for the coupling between3-aminoquinuclidine and benzisothiazole carboxylic acids to formcarboxamide derivatives.

To a solution of 6-methoxybenzisothiazole-3-carboxylic acid (61 mg, 0.30mmol) in a 5/1 mixture of tetrahydrofuran/N,N-dimethylformamide (12 mL)was added diisopropylethylamine (0.2 mL, 1.1 mmol) and (115 mg, 0.6mmol) 3-(R)-aminoquinuclidine dihydrochloride. The mixture was cooled to0° C., and HATU (115 mg, 0.3 mmol) was added in one portion. Thereaction mixture was allowed to warm to rt and was maintained overnight.The mixture was partitioned between saturated aqueous potassiumcarbonate solution and a 95/5 mixture of dichloromethane/methanol. Theaqueous layer was extracted with 95/5 dichloromethane/methanol (2×), andthe combined organic layers were washed with brine and dried over sodiumsulfate. The crude product was purified by chromatography (90/10/1dichloromethane/methanol/ammonium hydroxide) or by preparative HPLC,thus providing the amide in 75% yield as a colorless solid.

The following compounds were prepared using this method:

Example 58N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure B in 17% yield. ¹H NMR (CD₃OD) δ 8.85 (d,J=9.0, 1H), 8.49 (s, 1H), 8.13 (s, 1H), 7.48 (d, J=9.0, 1H), 4.55 (m,1H), 3.88-3.80 (m, 1H), 3.53-3.30 (m, 5H), 2.40 (m, 1H), 2.32-2.27 (m,1H), 2.16-2.10 (m, 2H), 1.99-1.91 (m, 1H); LC/MS (EI) t_(R) 4.58, m/z372 (M⁺+1).

Example 59N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure B in 37% yield. LC/MS (EI) t_(R) 4.42, m/z 332(M⁺+1).

Example 60N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure B in 12% yield. LC/MS (EI) t_(R) 4.31, m/z 332(M⁺+1).

Example 61N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure B in 41% yield. LC/MS (EI) t_(R) 4.62, m/z 372(M⁺+1).

Example 62N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure B in 36% yield. LC/MS (EI) t_(R) 4.34, m/z 358(M⁺+1).

Example 63N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure B in 53% yield. LC/MS (EI) t_(R) 4.33, m/z 358(M⁺+1).

Procedure C.

Procedure C provides a method for the coupling between3-aminoquinuclidine and carboxylic acids to form carboxamidederivatives.

To a solution of the carboxylic acid (4.77 mmol) inN,N-dimethylformamide (14 mL) was added N,N-diisopropylethylamine (19mmol) and 3-aminoquinuclidine dihydrochloride (4.29 mmol). The reactionmixture was maintained at room temperature for 30 min under nitrogen andthen HATU (4.76 mol) was added. After 18 h, the reaction mixture wasfiltered through Celite (methanol rinse) and was divided equally amongst3 SCX columns. The columns were washed with methanol (100 mL each) andthe basic components were eluted with 2 M ammonia in methanol (100 mLeach) and concentrated. The residue was purified by chromatography [1/1to 0/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammoniumhydroxide)] or by preparative HPLC, thus providing the product in15%-50% yield.

The following compounds were prepared using this method:

Example 64N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide

Prepared using Procedure C in 22% yield. ¹H NMR (CD₃OD) δ 8.07 (s, 1H),7.53 (d, J=8.4, 1H), 7.38 (d, J=8.4, 1H), 4.25 (m, 1H), 4.08 (m, 2H),3.60 (m, 2H), 3.36 (m, 1H), 3.15 (m, 1H), 3.0-2.8 (m, 5H), 2.11 (m, 1H),2.05 (m, 1H), 2.0-1.7 (m, 6H), 1.62 (m, 1H); LC/MS (EI) t_(R) 3.44, m/z355 (M⁺+1).

Example 65N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(hydroxy)-1H-indazole-3-carboxamide

Prepared using Procedure C or Procedure AA. ¹H NMR (400 MHz, Me₂SO-d₆) δ13.30 (s, 1H), 9.32 (s, 1H), 8.07 (d, J=7.6, 1H), 7.43 (m, 1H), 6.94 (m,1H), 4.01 (m, 1H), 3.12 (m, 1H), 2.93 (m, 1H), 2.72 (m, 4H), 1.89 (m,1H), 1.80 (m, 1H), 1.61 (m, 2H), 1.33 (m, 1H); LC/MS (EI) m/z 288(M⁺+1).

Example 66N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure C or Procedure AA in 11% yield. LC/MS (EI)t_(R) 2.35, m/z 288 (M⁺+1).

Example 67N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure C or Procedure AA in 11% yield. LC/MS (EI)t_(R) 2.37, m/z 287 (M⁺+1).

Example 68N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure C in 17% yield. LC/MS (EI) t_(R) 4.85, m/z 355(M⁺+1).

Example 69N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure C in 14% yield. LC/MS (EI) t_(R) 4.84, m/z 355(M⁺+1).

Example 70N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-(trifluoromethoxy)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure C in 41% yield. LC/MS (EI) t_(R) 4.71, m/z 355(M⁺+1).

Example 71N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-(trifluoromethoxy)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure C in 41% yield. LC/MS (EI) t_(R) 4.73, m/z 355(M⁺+1).

Example 72N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(nitro)-1H-indazole-3-carboxamide

Prepared using Procedure C in 73% yield. LC/MS (EI) t_(R) 3.43, m/z 316(M⁺+1).

Example 73N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(hydroxy)-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure C or Procedure AA in 70% yield. LC/MS (EI)t_(R) 2.75, m/z 304 (M⁺+1).

Example 74N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-nitro-1H-indazole-3-carboxamide

Prepared using Procedure C in 18% yield. LC/MS (EI) t_(R) 2.42, m/z 316(M⁺+1).

Example 75N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-nitro-1H-indazole-3-carboxamide

Prepared using Procedure C in 31% yield. LC/MS (EI) t_(R) 3.18, m/z 316(M⁺+1).

Example 76N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide

Prepared using Procedure C in 23% yield. LC/MS (EI) t_(R) 3.33, m/z 355(M⁺+1).

Example 77N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(nitro)-1H-indazole-3-carboxamide

Prepared using Procedure C in 28% yield. LC/MS (EI) t_(R) 2.43, m/z 316(M⁺+1).

Example 78N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-hydroxytetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide

Prepared using Procedure C in 20% yield. LC/MS (EI) t_(R) 2.39, m/z 371(M⁺+1).

Example 79N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-hydroxytetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide

Prepared using Procedure C in 30% yield. LC/MS (EI) t_(R) 2.39, m/z 371(M⁺+1).

Example 80N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-(nitro)-1H-indazole-3-carboxamide

Prepared using Procedure C in 17% yield. LC/MS (EI) t_(R) 2.99, m/z 316(M⁺+1).

Example 81N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure C in 15% yield. LC/MS (EI) t_(R) 3.20, m/z 353(M⁺+1).

Example 82N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide

Prepared using Procedure C in 21% yield. LC/MS (EI) t_(R) 3.90, m/z 353(M⁺+1).

Example 83N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-4-bromo-5-methoxy-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure C in 26% yield. LC/MS (EI) t_(R) 2.54, m/z381/383 (M⁺+1).

Example 84N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-bromo-5-methoxy-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure C in 12% yield. LC/MS (EI) t_(R) 2.54, m/z381/383 (M⁺+1).

Example 85N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-4-nitro-1H-indazole-3-carboxamide

Prepared using Procedure C in 25% yield. LC/MS (EI) t_(R) 4.73, m/z394/396 (M⁺+1).

Example 86N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(formyl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure C in 51% yield. LC/MS (EI) t_(R) 2.35, m/z 299(M⁺+1).

Example 87N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide

Prepared using Procedure C in 59% yield. LC/MS (EI) t_(R) 2.37, m/z 355(M⁺+1).

Example 88N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide

Prepared using Procedure C in 52% yield. LC/MS (EI) t_(R) 3.22, m/z 355(M⁺+1).

Example 89N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxamide

Prepared using Procedure C in 81% yield. LC/MS (EI) t_(R) 5.02, m/z 383(M⁺+1).

Example 90N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(ethyl)-1H-indazole-3-carboxamide

Prepared using Procedure C in 64% yield. LC/MS (EI) t_(R) 3.94, m/z377/379 (M⁺+1).

Example 91N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-(ethyl)-1H-indazole-3-carboxamide

Prepared using Procedure C in 72% yield. LC/MS (EI) t_(R) 3.90, m/z377/379 (M⁺+1).

Example 92N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(cyclopropylmethyl)-1H-indazole-3-carboxamide

Prepared using Procedure C in 70% yield. LC/MS (EI) t_(R) 4.20, m/z403/405 (M⁺+1).

Example 93N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxamide

Prepared using Procedure C in 61% yield. LC/MS (EI) t_(R) 4.10, m/z431/433 (M⁺+1).

Example 94N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(dimethylamino)methyl]-1H-indazole-3-carboxamidedihydroformate

Prepared using Procedure C in 35% yield. LC/MS (EI) t_(R) 1.30, m/z 328(M⁺+1).

Example 95N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(diethylamino)methyl]-1H-indazole-3-carboxamidedihydroformate

Prepared using Procedure C in 29% yield. LC/MS (EI) t_(R) 1.32, m/z 356(M⁺+1).

Example 96N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(pyrrolidin-1-yl)methyl]-1H-indazole-3-carboxamidedihydroformate

Prepared using Procedure C in 39% yield. LC/MS (EI) t_(R) 1.34, m/z 354(M⁺+1).

Example 97N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(1-benzylpyrrolidin-3-yl)oxy]-1H-indazole-3-carboxamidedihydroformate

Prepared using Procedure C in 33% yield. LC/MS (EI) t_(R) 2.35, m/z 446(M⁺+1).

Example 98N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-ethyl-6-methoxy-1H-indazole-3-carboxamide

Prepared using Procedure C in 7% yield. LC/MS (EI) t_(R) 2.78, m/z 329(M⁺+1).

Example 99N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-ethyl-5-trifluoromethoxy-1H-indazole-3-carboxamide

Prepared using Procedure C in 1% yield. LC/MS (EI) t_(R) 3.83, m/z 383(M⁺+1).

Example 100N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-6-methoxy-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure C in 7% yield. LC/MS (EI) t_(R) 3.56, m/z 355(M⁺+1).

Example 101N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure C in 8% yield. LC/MS (EI) t_(R) 3.42, m/z 325(M⁺+1).

Example 102N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-5-trifluoromethoxy-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure C in 5% yield. LC/MS (EI) t_(R) 3.99, m/z 409(M⁺+1).

Example 103N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(hydroxy)-1H-indazole-3-carboxamide

Prepared using Procedure C in 40% yield. LC/MS (EI) t_(R) 9.80 [95/5 to5/95 water (0.1% formic acid)/acetonitrile (0.1% formic acid)], m/z 287(M⁺+1).

Example 104N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(hydroxymethyl)-1H-indazole-3-carboxamide

Prepared from Example 86 by sodium borohydride reduction in 12% yield.LC/MS (EI) t_(R) 1.99, m/z 301 (M⁺+1).

Example 105N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclopentylamino)-1H-indazole-3-carboxamide

Prepared using Procedure C. The acid was prepared from ethyl5-nitro-1H-indazole-3-carboxylate via reduction, reductive amination,and saponification in 46% yield. LC/MS (EI) t_(R) 1.92, m/z 354 (M⁺+1).

Procedure D.

Procedure D provides a method for the coupling between3-aminoquinuclidine and carboxylic acids to form carboxamidederivatives.

The coupling reaction and purification was performed according toprocedures A and C (indazoles, benzthiazoles) or according to procedureB (benzisothiazoles). The free base was dissolved in methanol (3.5mL/mmol starting acid) and treated with 1N hydrochloric acid in ether(3.5 mL/mmol starting acid). The resulting suspension was diluted withether (7 mL/mmol starting acid) and was maintained at room temperaturefor 2 h. The solids were collected by filtration, rinsed with ether, anddried, thus providing the hydrochloride salt in 40-60% yield.

The following compounds were prepared using this method:

Example 106N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamidehydrochloride

Prepared using Procedure D in 42% yield. ¹H NMR (500 MHz, Me₂SO-d₆) δ14.02 (s, 1H), 10.42 (s, 1H), 8.89 (d, J=7.0, 1H), 8.27 (s, 1H), 7.67(d, J=8.5, 1H), 7.49 (dd, J=8.0, 1.0, 1H), 4.44 (m, 1H), 3.62 (m, 1H),3.34 (m, 2H), 3.21 (m, 4H), 2.21 (m, 1H), 2.09 (m, 1H), 1.93 (m, 2H),1.73 (m, 1H); LC/MS (EI) t_(R) 2.61, m/z 295 (M⁺+1).

Example 107N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydrochloride

Prepared using Procedure D in 56% yield. LC/MS (EI) t_(R) 5.53, m/z 368(M⁺+1).

Example 108N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamidehydrochloride

Prepared using Procedure D in 29% yield. LC/MS (EI) t_(R) 3.20, m/z 353(M⁺+1).

Example 109N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydrochloride

Prepared using Procedure D. LC/MS (EI) t_(R) 13.28 [Analytical HPLC wasperformed on 4.6 mm×250 mm YMC 0DS-AQ S-5 120 m columns using a gradientof 05/95 to 95/05 acetonitrile (0.05% trifluoroacetic acid)/water (0.05%trifluoroacetic acid) over 35 min], m/z 368 (M⁺+1).

Example 110N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydrochloride

Prepared using Procedure D in 57% yield. LC/MS (EI) t_(R) 14.00, m/z 367(ES-Neg) (M⁺).

Example 111N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamidehydrochloride

Prepared using Procedure D in 60% yield. LC/MS (EI) t_(R) 5.13, m/z 355(M⁺+1).

Example 112N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydrochloride

Prepared using Procedure D in 68% yield. LC/MS (EI) t_(R) 2.58, m/z 354(M⁺+1).

Example 113N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydrochloride

Prepared using Procedure D in 38% yield. LC/MS (EI) t_(R) 2.58, m/z 354(M⁺+1).

Example 114N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamidehydrochloride

Prepared using Procedure D in 68% yield. LC/MS (EI) t_(R) 2.53, m/z 301(M⁺+1).

Procedure E

Procedure E provides a method for the formation of carboxamidederivatives from methyl 3-quinuclidinecarboxylic acid ester.

To a solution of the amine in toluene was added 1.0 M solution oftrimethylaluminum in toluene (1.1 eq) at 0° C. After 30 min, anadditional 1.1 eq of trimethylaluminum was added followed by a solutionof methyl 3-quinuclidinecarboxylic acid ester hydrochloride salt (1.1eq) in dioxane (5 mL). The reaction mixture was heated at 70° C. for 10h, allowed to cool to rt, and was poured onto a cold (0° C.), aqueoussolution of sodium bicarbonate. The aqueous layer was extracted with 5%methanol in methylene chloride (2×30 mL) and the combined organic layerswere washed with brine and concentrated. The residue was purified bypreparative HPLC.

Procedure F

Procedure F provides a method for the reduction of the carboxamide toform secondary amine derivatives.

To a solution of the amide (50 mg) in tetrahydrofuran (4 mL) was addedlithium aluminum hydride (4.0 eq). The reaction mixture was heated atreflux for 4 h, was cooled to 0° C., and was cautiously quenched withethanol. The resultant slurry was poured onto ice water and extractedwith 5% methanol in dichloromethane (3×) and the combined organic layerswere concentrated. The residue was purified by preparative HPLC.

Procedure G.

Procedure G provides a method for the coupling between brominated andiodinated aminoquinuclidinecarboxamides and boronic acids to formaryl-substituted derivatives.

In a 5 mL microwave reaction vessel was added the bromide (0.286 mmol),the boronic acid (0.588 mmol), tris(dibenzylideneacetone)dipalladium (0)(0.0289 mmol), tri-tert-butylphosphine tetrafluoroborate (0.0579 mmol),and potassium carbonate (0.810 mmol). The vessel was evacuated,back-filled with argon gas, and the contents diluted withN,N-dimethylformamide (5.0 mL). The vessel was sealed and subjected tomicrowave irradiation at 200° C. for 600 s. The contents of the reactionwere filtered through Celite (methanol wash) and loaded on a 5 g SCXcolumn. The column was washed with methanol (50 mL) and the product waseluted with 2 M ammonia in methanol and concentrated. The residue waspurified by preparative HPLC, thus providing the product in 15-40%yield.

The following compounds were prepared using this method:

Example 115N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(3-thienyl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure G or C in 37% yield. ¹H NMR (CD₃OD) δ 8.39 (s,1H), 7.57 (d, J=9.1, 1H), 7.46 (m, 1H), 7.39 (d, J=9.1, 1H), 7.36 (m,1H), 7.23 (m, 1H), 4.03 (m, 1H), 3.79 (s, 3H), 3.59 (m, 1H), 3.3-3.2 (m,5H), 2.81 (m, 1H), 2.10 (m, 1H), 1.97 (m, 2H), 1.79 (m, 1H). LC/MS (EI)t_(R) 2.60, m/z 383 (M⁺+1).

Example 116N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(2-thienyl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure G or C in 12% yield. LC/MS (EI) t_(R) 2.62, m/z383 (M⁺+1).

Example 117N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(2-thienyl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure G or C in 16% yield. LC/MS (EI) t_(R) 2.37, m/z383 (M⁺+1).

Procedure H.

Procedure H provides a method for the coupling between brominated3-aminoquinuclidinecarboxamides and Grignard reagents to formalkyl-substituted derivatives.

A 5 mL microwave reaction vessel was charged withbis(triphenylphosphine)palladium (II) chloride (0.030 mmol, 0.1 eq) andthe bromide (0.30 mmol). The vessel was evacuated and back-filled withargon gas. In a separate reaction vessel, solution of the Grignard (1.2mmol, 4 eq) was added to a 0.5 M solution of zinc chloride (1.2 mmol, 4eq) in tetrahydrofuran at rt. The suspension was maintained for 30 minand the entire contents were transferred to the reaction vessel viacannula. The vessel was sealed and subjected to microwave irradiation at100° C. for 600 sec with a pre-stir time of 60 s. The reaction wasquenched with acetic acid (0.5 mL), diluted with methanol, and wastransferred to a SCX column. The column was washed with methanol (50 mL)and the product was eluted with 2 M ammonia in methanol (50 mL) andconcentrated. The residue was purified by chromatography [90/10/1dichloromethane/methanol/ammonium hydroxide or 1/1 to 0/1 ethylacetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] or bypreparative HPLC, thus providing the product in 20-50% yield.

The Grignard reagent of thiazole is commercially available.Alternatively, the aryllithium and the corresponding arylzinc reagentcan be generated according to the procedure outlined by Reeder, M. R.;et. al. Org. Proc. Res. Devel. 2003, 7, 696. The zinc reagents ofoxazole, 1-methylimidazole, and related reagents were prepared accordingto this procedure.

The following compounds were prepared using this method:

Example 118N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyclopentyl-1H-indazole-3-carboxamide

Prepared using Procedure H in 21% yield. ¹H NMR (CD₃OD) δ 8.07 (s, 1H),7.50 (d, J=8.7, 1H), 7.36 (d, J=8.7, 1H), 4.21 (m, 1H), 3.36 (m, 1H),3.15 (m, 1H), 3.02 (m, 1H), 3.0-2.8 (m, 4H), 2.2-2.0 (m, 3H), 2.0-1.5(m, 10H). LC/MS (EI) t_(R) 5.11, m/z 339 (M⁺+1).

Example 119N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H in 37% yield. LC/MS (EI) t_(R) 4.28, m/z 354(M⁺+1).

Example 120N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H in 18% yield. LC/MS (EI) t_(R) 2.54, m/z 354(M⁺+1).

Example 121N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H in 18% yield. LC/MS (EI) t_(R) 2.58, m/z 354(M⁺+1).

Example 122N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H in 12% yield. LC/MS (EI) t_(R) 3.96, m/z 354(M⁺+1).

Example 123N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(prop-1-yn-1-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H in 24% yield. LC/MS (EI) t_(R) 4.97, m/z 309(M⁺+1).

Example 124N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide

Prepared using Procedure H in 71% yield. LC/MS (EI) t_(R) 2.58, m/z 338(M⁺+1).

Example 125N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide

Prepared using Procedure H in 85% yield. LC/MS (EI) t_(R) 2.61, m/z 338(M⁺+1).

Example 126N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide

Prepared using Procedure H in 55% yield. LC/MS (EI) t_(R) 3.12, m/z 338(M⁺+1).

Example 127N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide

Prepared using Procedure H in 72% yield. LC/MS (EI) t_(R) 2.64, m/z 338(M⁺+1).

Example 128N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H in 11% yield. LC/MS (EI) t_(R) 1.21, m/z 351(M⁺+1).

Example 129N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H in 18% yield. LC/MS (EI) t_(R) 1.23, m/z 351(M⁺+1).

Example 130N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyclopentyl-1H-indazole-3-carboxamide

Prepared using Procedure H in 25% yield. LC/MS (EI) t_(R) 5.27, m/z 339(M⁺+1).

Example 131N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclopentyl-1H-indazole-3-carboxamide

Prepared using Procedure H in 30% yield. LC/MS (EI) t_(R) 5.11, m/z 339(M⁺+1).

Example 132N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclopentyl-1H-indazole-3-carboxamide

Prepared using Procedure H in 38% yield. LC/MS (EI) t_(R) 5.10, m/z 339(M⁺+1).

Example 133N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H in 11% yield. LC/MS (EI) t_(R) 5.37, m/z 353(M⁺+1).

Example 134N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H in 12% yield. LC/MS (EI) t_(R) 5.33, m/z 353(M⁺+1).

Example 135N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamide

Prepared using Procedure H in 32% yield. LC/MS (EI) t_(R) 5.37, m/z 353(M⁺+1).

Example 136N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamide

Prepared using Procedure H in 10% yield. LC/MS (EI) t_(R) 5.39, m/z 353(M⁺+1).

Example 137N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(propyl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H in 6% yield. LC/MS (EI) t_(R) 4.84, m/z 315(M⁺+1).

Example 138N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(ethyl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H in 19% yield. LC/MS (EI) t_(R) 4.48, m/z 299(M⁺+1).

Example 139N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamide

Prepared using Procedure H in 43% yield. LC/MS (EI) t_(R) 4.98, m/z 368(M⁺+1).

Example 140N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamide

Prepared using Procedure H in 30% yield. LC/MS (EI) t_(R) 4.96, m/z 368(M⁺+1).

Example 141N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamide

Prepared using Procedure H in 30% yield. LC/MS (EI) t_(R) 5.01, m/z 368(M⁺+1).

Example 142N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamide

Prepared using Procedure H in 56% yield. LC/MS (EI) t_(R) 4.59, m/z 368(M⁺+1).

Example 143N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(butyl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H in 15% yield. LC/MS (EI) t_(R) 5.41, m/z 327(M⁺+1).

Example 144N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-cyclopropyl-5-methoxy-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H in 20% yield. LC/MS (EI) t_(R) 2.73, m/z 341(M⁺+1).

Example 145N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-ethyl-5-methoxy-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H in 10% yield. LC/MS (EI) t_(R) 2.42, m/z 329(M⁺+1).

Example 146N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H in 24% yield. LC/MS (EI) t_(R) 4.98, m/z 368(M⁺+1).

Example 147N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H in 61% yield. LC/MS (EI) t_(R) 3.63, m/z 382(M⁺+1).

Example 148N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-cyclopropylmethyl-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H in 10% yield. LC/MS (EI) t_(R) 3.97, m/z 408(M⁺+1).

Example 149N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethyl)-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H in 18% yield. LC/MS (EI) t_(R) 3.87, m/z 436(M⁺+1).

Example 150N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H in 32% yield. LC/MS (EI) t_(R) 3.67, m/z 382(M⁺+1).

Example 151N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure H in 16% yield. LC/MS (EI) t_(R) 5.20, m/z 371(M⁺+1).

Example 152N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure H in 36% yield. LC/MS (EI) t_(R) 5.16, m/z 371(M⁺+1).

Example 153N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(methyl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure H or C in 13% yield. LC/MS (EI) t_(R) 3.18, m/z285 (M⁺+1).

Procedure I.

Procedure I provides a method for the coupling between brominated3-aminoquinuclidinecarboxamides and acetylenes to formalkynyl-substituted derivatives.

A 5 mL microwave reaction vessel was charged withbis(triphenylphosphine)palladium (II) chloride (0.0597 mmol, 0.1 eq),copper (I) iodide (0.0719 mmol, 0.12 eq.), triphenylphosphine (0.124mmol, 0.2 eq.), and the bromide (0.578 mmol). The vessel was evacuatedand back-filled with argon gas. The alkyne (0.71 mmol, 1.2 eq),diethylamine (3.5 mL), and N,N-dimethylformamide (1.5 mL) were added andthe vessel was sealed and subjected to microwave irradiation at 120° C.for 1500 sec. The reaction was reduced under vacuum to ˜1.5 mL and wastransferred to a SCX column. The column was washed with methanol (50 mL)and the product was eluted with 2 M ammonia in methanol (50 mL) andconcentrated. The residue was purified by chromatography [1/1 to 0/1ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] toprovide the silylacetylene in 90-95% yield. The silane was dissolved intetrahydrofuran (2.5 mL) and was treated with tetrabutylammoniumfluoride (0.6 mL of a 1 M solution in tetrahydrofuran). The reactionmixture was maintained for 11 h and was transferred to a SCX column. Thecolumn was washed with methanol (50 mL) and the product was eluted with2 M ammonia in methanol (50 mL) and concentrated. The residue waspurified by preparative HPLC, thus providing the product in 40-60%yield.

The following compounds were prepared using this method:

Example 154N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure I in 36% yield. ¹H NMR (CD₃OD) δ 8.41 (s, 1H),8.33 (s, 1H), 7.58 (d, J=8.7, 1H), 7.49 (dd, J=8.7, 1.4, 1H), 4.53 (m,1H), 3.82 (m, 1H), 3.47 (s, 1H), 3.31 (m, 5H), 2.38 (m, 1H), 2.27 (m,1H), 2.10 (m, 2H), 1.93 (m, 1H); LC/MS (EI) t_(R) 2.61, m/z 295 (M⁺+1).

Example 155N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure I in 40% yield. LC/MS (EI) t_(R) 2.73, m/z 295(M⁺+1).

Example 156N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure I in 29% yield. LC/MS (EI) t_(R) 2.73, m/z 295(M⁺+1).

Example 157N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure I in 30% yield. LC/MS (EI) t_(R) 2.63, m/z 295(M⁺+1).

Example 158N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(pent-1-yn-1-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure I in 37% yield. LC/MS (EI) t_(R) 5.28, m/z 337(M⁺+1).

Example 159N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(phenylethynyl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure I in 36% yield. LC/MS (EI) t_(R) 5.46, m/z 371(M⁺+1).

Example 160N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure I in 9% yield. LC/MS (EI) t_(R) 4.24, m/z 312(M⁺+1).

Example 161N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure I in 5% yield. LC/MS (EI) t_(R) 5.22, m/z 312(M⁺+1).

Procedure J.

Procedure J provides a method for the coupling between brominated3-aminoquinuclidinecarboxamides and cyclic alkenes to formcycloalkenyl-substituted derivatives.

A 5 mL microwave reaction vessel was charged with palladium (II) acetate(0.012 mmol, 0.04 eq), tri-o-tolylphosphine (0.030 mmol, 0.1 eq.), andthe bromide (0.358 mmol). The vessel was evacuated and back-filled withargon gas. The alkene (0.30 mmol), diisopropylethylamine (63 μL), andN,N-dimethylformamide (2.8 mL) were added and the vessel was sealed andsubjected to microwave irradiation at 220° C. for 300 sec. The reactionwas transferred to a SCX column and the column was washed with methanol(50 mL). The product was eluted with 2 M ammonia in methanol (50 mL) andconcentrated. The residue was purified by chromatography [1/1 to 0/1ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] andwas further purified by preparative HPLC, thus providing the product in7-40% yield.

The following compounds were prepared using this method:

Example 162N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclohex-1-en-1-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure J in 7% yield. ¹H NMR (CD₃OD) δ 8.48 (s, 1H),8.05 (s, 1H), 7.53 (d, J=8.7, 1H), 7.37 (dd, J=8.7, 1.6, 1H), 5.77 (m,1H), 4.52 (m, 1H), 3.81 (m, 1H), 3.35 (m, 5H), 2.38 (m, 1H), 2.27 (m,1H), 2.10 (m, 2H), 1.93 (m, 1H); LC/MS (EI) t_(R) 5.14, m/z 351 (M⁺+1).

Example 163N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-formylcyclohex-1-en-1-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure J in 1% yield. LC/MS (EI) t_(R) 4.91, m/z 379(M⁺+1).

Example 164N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydrofuran-3-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure J followed by hydrogenation in 2% yield. LC/MS(EI) t_(R) 3.59, m/z 341 (M⁺+1).

Procedure K.

Procedure K provides a method for the coupling between brominated3-aminoquinuclidinecarboxamides and nickel (II) cyanide to formcyano-substituted derivatives.

A 5 mL microwave reaction vessel was charged with nickel (II) cyanide(3.11 mmol, 5.4 eq) and the bromide (0.578 mmol). The vessel wasevacuated, back-filled with argon gas, and diluted withN-methylpyrrolidinone (5.0 mL). The vessel was sealed and subjected tomicrowave irradiation at 200° C. for 2400 sec. The reaction wastransferred to a SCX column and the column was washed with methanol (50mL). The product was eluted with 2 M ammonia in methanol (50 mL) andconcentrated. The residue was purified by preparative HPLC, thusproviding the product in 10-40% yield.

-   Literature Reference: Arvella, R. K.; Leadbeater, N.E. J. Org. Chem.    2003, 68, 9122.

The following compounds were prepared using this method:

Example 165N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure K in 41% yield. ¹H NMR (CD₃OD) δ 8.94 (d,J=8.5, 1H), 8.63 (s, 1H), 7.83 (d, J=8.5, 1H), 4.55 (m, 1H), 3.89-3.81(m, 1H), 3.53-3.31 (m, 5H), 2.42 (m, 1H), 2.26-2.16 (m, 1H), 2.14-2.03(m, 2H), 1.99-1.91 (m, 1H); LC/MS (EI) t_(R) 3.68, m/z 313 (M⁺+1).

Example 166N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure K in 39% yield. LC/MS (EI) t_(R) 2.59, m/z 296(M⁺+1).

Example 167N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure K in 52% yield. LC/MS (EI) t_(R) 2.55, m/z 296(M⁺+1).

Example 168N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure K in 18% yield. LC/MS (EI) t_(R) 2.47, m/z 296(M⁺+1).

Example 169N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure K in 42% yield. LC/MS (EI) t_(R) 2.47, m/z 296(M⁺+1).

Example 170N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure K in 48% yield. LC/MS (EI) t_(R) 2.99, m/z 313(M⁺+1).

Example 171N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamidehydrotrifluoroacetate

Prepared using Procedure K in 41% yield. LC/MS (EI) t_(R) 3.68, m/z 313(M⁺+1).

Example 172N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamidehydrotrifluoroacetate

Prepared using Procedure K in 48% yield. LC/MS (EI) t_(R) 2.99, m/z 313(M⁺+1).

Procedure L.

Procedure L provides a method for the coupling between brominated3-aminoquinuclidinecarboxamides and phenols to form biaryl etherderivatives.

A 2.5 mL microwave reaction vessel was charged with copper (II) triflate(0.144 mmol, 0.5 eq.), cesium carbonate (0.565 mmol, 2 eq.), benzoicacid (0.402 mmol, 1.4 eq.), and the bromide (0.284 mmol). The vessel wasevacuated and back-filled with argon gas. A 0.5 M solution of the phenolin N,N-dimethylformamide (1.2 mL, 0.60 mmol, 2.1 eq), andN,N-dimethylformamide (1.3 mL) were added and the vessel was sealed andsubjected to microwave irradiation at 200° C. for 2400 sec. The reactionmixture was transferred to a SCX column and the column was washed withmethanol (50 mL). The product was eluted with 2 M ammonia in methanol(50 mL) and concentrated. The residue was purified by chromatography[1/1 to 0/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammoniumhydroxide)] and was further purified by preparative HPLC, thus providingthe product in 10-40% yield.

The following compounds were prepared using this method:

Example 173N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-phenoxy-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure L in 2% yield. ¹H NMR (CD₃OD) δ 8.53 (s, 1H),7.71 (d, J=1.8, 1H), 7.63 (d, J=9.0, 1H), 7.37 (dd, J=8.4, 7.5, 2H),7.23 (dd, J=9.0. 2.3, 1H), 7.12 (t, J=7.4, 2H), 7.01 (d, J=8.8, 1H),4.52 (m, 1H), 3.81 (m, 1H), 3.35 (m, 5H), 2.38 (m, 1H), 2.27 (m, 1H),2.10 (m, 2H), 1.93 (m, 1H); LC/MS (EI) t_(R) 5.02, m/z 363 (M⁺+1).

Procedure M.

Procedure M provides a method for the coupling between aniline or phenolbearing aminoquinuclidinecarboxamides and alkylating agents to formsecondary aniline- or ether-substituted derivatives.

To a solution ofN-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1,2-benzisothiazole-3-carboxamide(0.400 mol) in N,N-dimethylformamide (6 mL) was added potassiumcarbonate (2.00 mol) and cyclopropylmethyl bromide (0.47 mmol). Thereaction was maintained for 16 h and the solvent was removed in vacuo.The residue was extracted with 10/1 dichloromethane/methanol (3×) andthe combined extracts were concentrated. The residue was purified bypreparative HPLC using an 8 min gradient of 95/5 to 20/80 water (0.1%formic acid)/acetonitrile (0.1% formic acid), thus providing the productin 32% yield.

The following compounds were prepared by this method:

Example 174N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(2-methoxyethoxy)propoxy]-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure M in 30% yield. ¹H NMR (CD₃OD) δ 8.55 (d,J=9.0, 1H), 8.38 (broad, 1H), 7.37 (s, 1H), 7.05 (d, J=9.0, 1H), 4.55(m, 1H), 3.95 (t, J=9.0, 1H), 3.70-3.45 (m, 11H), 3.31 (s, 3H), 2.40 (m,1H), 2.30 (m, 1H), 2.15 (m, 2H), 2.05 (m, 2H), 1.30 (t, J=6.0, 2H).LC/MS (EI) t_(R) 2.88, m/z 420 (M⁺+1).

Example 175N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure M in 32% yield. LC/MS (EI) t_(R) 3.48, m/z 358(M⁺+1).

Procedure N.

Procedure N provides a method for the hydrolysis of nitrile-substituted3-aminoquinuclidinecarboxamides to form carboxyl-substitutedderivatives.

A 2.5 mL microwave reaction vessel was charged with the nitrile (0.195mmol), water (2.0 mL), and 2 N sodium hydroxide (0.5 mL). The vessel wassealed and subjected to microwave irradiation at 200° C. for 1800 sec.The reaction was acidified with acetic acid (˜1.5 mL) and wastransferred to a SCX column. The column was washed with methanol (50 mL)and the product was eluted with 2 M ammonia in methanol (50 mL) andconcentrated. The residue was purified by preparative HPLC, thusproviding the product in 5-30% yield.

The following compounds were prepared using this method:

Example 1763-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazole-6-carboxylicacid hydroformate

Prepared using Procedure N in 3% yield. ¹H NMR (CD₃OD) δ 8.39 (s, 1H),8.25 (s, 1H), 8.21 (d, J=8.6, 1H), 7.89 (dd, J=8.6, 1.2, 1H), 4.53 (m,1H), 3.84 (m, 1H), 3.37 (m, 5H), 2.39 (m, 1H), 2.28 (m, 1H), 2.11 (m,2H), 1.94 (m, 1H); LC/MS (EI) t_(R) 2.37, m/z 315 (M⁺+1).

Procedure O.

Procedure O provides a method for the coupling between brominated3-aminoquinuclidinecarboxamides and amines to form amino-substitutedderivatives.

In a 5 mL microwave reaction vessel was added the bromide (133 mg, 0.37mmol), tris(dibenzylideneacetone)dipalladium (0) (34 mg, 0.04 mmol),cesium bicarbonate (213 mg, 1.1 mmol), and(2′-dicyclohexylphosphanylbiphenyl-2-yl)dimethylamine (30 mg, 0.07mmol). The vial was then evacuated and back-filled with argon gas. Themixture of solids was then diluted with the amine (0.7 mL), dioxane (1mL), and triethylamine (0.5 mL) and the reaction vessel was sealed. Thereaction mixture was subjected to microwave irradiation at 120° C. for1800 s. The reaction mixture was filtered through a plug of Celite andconcentrated in vacuo. The crude product was purified by chromatography(90/10/1 dichloromethane/methanol/ammonium hydroxide), thus providingthe product in 34% yield as a colorless solid.

The following compounds were prepared using this method:

Example 177N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-indazole-3-carboxamide

Prepared using Procedure O in 13% yield. ¹H NMR (CD₃OD) 8 d 8.09 (dd,J=1.9, 0.7, 1H), 7.55 (dd, J=8.8, 0.7, 1H), 7.41 (dd, J=8.8, 1.9, 1H),5.82 (s, 2H), 4.22 (m, 1H), 3.35 (m, 1H), 3.03 (m, 1H), 3.0-2.8 (m, 4H),2.06 (m, 1H), 2.00 (m, 1H), 1.99 (s, 6H), 1.79 (m, 2H), 1.55 (m, 1H);LC/MS (EI) t_(R) 5.00, m/z 364 (M⁺+1).

Example 178N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1H-pyrrol-1-yl)-1H-indazole-3-carboxamide

Prepared using Procedure O in 7% yield. LC/MS (EI) t_(R) 4.94, m/z 336(M⁺+1).

Example 179N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1H-pyrrol-1-yl)-1H-indazole-3-carboxamide

Prepared using Procedure O in 26% yield. LC/MS (EI) t_(R) 4.79, m/z 336(M⁺+1).

Procedure P.

Procedure P provides a method for the coupling between brominated3-aminoquinuclidinecarboxamides and cyclic, secondary amines to formamino-substituted derivatives.

A 2.5 mL microwave reaction vessel was charged withtris(dibenzylideneacetone)dipalladium (0) (0.060 mmol, 0.1 eq),[2′-(dimethylamino)biphenyl-2-yl]dicyclohexylphosphine (0.060 mmol, 0.1eq), and the bromide (0.550 mmol). The vessel was evacuated andback-filled with argon gas. The amine (0.66 mmol, 1.2 eq) and a 1 Msolution of lithium hexamethyldisilazide in tetrahydrofuran (1.7 mmol, 3eq) were added and the vessel was sealed and heated at 65° C. for 15 h.The reaction was transferred to a SCX column and the column was washedwith methanol (50 mL). The product was eluted with 2 M ammonia inmethanol (50 mL) and concentrated. The residue was purified bypreparative HPLC, thus providing the product in 30-50% yield.

-   Literature reference: Harris, M. C.; Huang, X.; Buchwald, S. L. Org.    Lett. 2002, 4, 2885.

The following compounds were prepared using this method:

Example 180N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-pyrrolidin-1-yl-1H-indazole-3-carboxamide

Prepared using Procedure P in 24% yield. ¹H NMR (CD₃OD) δ 7.43 (d,J=9.1, 1H), 7.20 (s, 1H), 6.98 (d, J=9.1, 1H), 4.20 (m, 1H), 3.5-3.2 (m,5H), 3.15 (m, 1H), 3.0-2.8 (m, 4H), 2.2-2.0 (m, 6H), 1.79 (m, 2H), 1.55(m, 1H); LC/MS (EI) t_(R) 2.53, m/z 340 (M⁺+1).

Example 181N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-cyclohexylpiperazin-1-yl)-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure P in 52% yield. LC/MS (EI) t_(R) 2.40, m/z 454(M⁺+1).

Example 182N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-ethylpiperazin-1-yl)-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure P in 51% yield. LC/MS (EI) t_(R) 1.57, m/z 400(M⁺+1).

Example 183N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[4-(3-furoyl)piperazin-1-yl]-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure P in 50% yield. LC/MS (EI) t_(R) 4.61, m/z 466(M⁺+1).

Example 184N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-ethoxypyrrolidin-1-yl)-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure P in 58% yield. LC/MS (EI) t_(R) 3.87, m/z 401(M⁺+1).

Example 185N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-ethoxypyrrolidin-1-yl)-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure P in 41% yield. LC/MS (EI) t_(R) 3.67, m/z 401(M⁺+1).

Example 186N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-methoxypyrrolidin-1-yl)-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure P in 19% yield. LC/MS (EI) t_(R) 3.63, m/z 387(M⁺+1).

Example 187N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-pyrrolidin-1-yl-1H-indazole-3-carboxamide

Prepared using Procedure P in 24% yield. LC/MS (EI) t_(R) 4.63, m/z 340(M⁺+1).

Example 188N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-piperidin-1-yl-1H-indazole-3-carboxamidehydrotrifluoroacetate

Prepared using Procedure P in 51% yield. LC/MS (EI) t_(R) 1.88, m/z 354(M⁺+1).

Example 189N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-piperidin-1-yl-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure P in 26% yield. LC/MS (EI) t_(R) 1.60, m/z 354(M⁺+1).

Example 190N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-morpholin-4-yl-1H-indazole-3-carboxamide

Prepared using Procedure P in 25% yield. LC/MS (EI) t_(R) 2.60, m/z 356(M⁺+1).

Example 191N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(morpholin-4-yl)-1H-indazole-3-carboxamide

Prepared using Procedure P in 16% yield. LC/MS (EI) t_(R) 2.42, m/z 356(M⁺+1).

Example 192N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-yl]-1-ethyl-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure P in 24% yield. LC/MS (EI) t_(R) 4.53, m/z 474(M⁺+1).

Example 193N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(benzyloxy)pyrrolidin-1-yl]-1-ethyl-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure P in 48% yield. LC/MS (EI) t_(R) 4.55 min, m/z474 (M⁺+1).

Example 194N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-yl]-1-(cyclopropylmethyl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure P in 51% yield. LC/MS (EI) t_(R) 4.67 min, m/z500 (M⁺+1).

Procedure Q

Procedure Q provides a method for the coupling between brominatedaminoquinuclidinecarboxamides and benzophenone imine to form anilinederivatives.

The mixture ofN-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisothiazole-3-carboxamide(6.30 mmol), palladium acetate (1.00 mmol), and9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos) (0.700 mmol)was evacuated and back-fill with Ar gas. The solids were diluted withtetrahydrofuran (150 mL) and treated with cesium carbonate (7.00 mmol)and benzophenone imine (6.80 mmol). The reaction mixture was heated atreflux for 16 h. The reaction mixture was concentrated and redissolvedin a mixture of tetrahydrofuran (90 mL) and 3 N hydrochloric acid (30mL). The reaction mixture was maintained for 2 h and was concentrated.The residue was purified by chromatography using a mixture of 70/30/1ethyl acetate/methanol//ammonium hydroxide, thus providing the anilinein 79% yield. The aniline was used directly in subsequent reactions.

The following compounds were prepared by this method:

Example 1956-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamide

Prepared using Procedure Q in 72% yield. LC/MS (EI) t_(R) 2.44, m/z 287(M⁺+1).

Example 1966-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure Q in 69% yield. LC/MS (EI) t_(R) 2.86, m/z 303(M⁺+1).

Example 1976-Amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure Q in 73% yield. LC/MS (EI) t_(R) 2.84, m/z 303(M⁺+1).

Example 1985-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxamide

Prepared using Procedure Q in 64% yield. LC/MS (EI) t_(R) 1.43, m/z 368(M⁺+1).

Example 1995-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-1H-indazole-3-carboxamide

Prepared using Procedure Q in 67% yield. LC/MS (EI) t_(R) 1.43, m/z 340(M⁺+1).

Example 2005-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-1H-indazole-3-carboxamide

Prepared using Procedure Q in 68% yield. LC/MS (EI) t_(R) 1.34, m/z 314(M⁺+1).

Example 2016-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-1H-indazole-3-carboxamide

Prepared using Procedure Q in 61% yield. LC/MS (EI) t_(R) 1.36, m/z 314(M⁺+1).

Procedure R

Procedure R provides a method for the reduction of nitroaminoquinuclidinecarboxamides to form aniline derivatives.

A mixture of the nitro compound (1.06 mmol) and 10% palladium on carbon(100 mg) in a Parr shaker bottle was diluted with methanol (100 mL). Thereaction vessel was pressurized to 30 psi with hydrogen gas and wasmaintained for 3 h. The reaction was evacuated, back-filled withnitrogen gas, and the catalyst removed by filtration through Celite. Theorganic layer was concentrated to provide the amine product (91%). Theaniline was used directly in subsequent reactions.

The following compounds were prepared by this method:

Example 2026-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide

Prepared using Procedure R in 4% yield. LC/MS (EI) t_(R) 1.85, m/z 386(M⁺+1).

Example 2035-Amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide

Prepared using Procedure R in 91% yield. LC/MS (EI) t_(R) 1.36, m/z 286(M⁺+1).

Example 2045-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide

Prepared using Procedure R in 95% yield. LC/MS (EI) t_(R) 1.30, m/z 286(M⁺+1).

Example 2054-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide

Prepared from Example 87 using Procedure R in 97% yield. LC/MS (EI)t_(R) 2.53, m/z 286 (M⁺+1).

Example 2067-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide

Prepared from the corresponding 6-bromo-7-nitro analog using Procedure Rin 11% yield. LC/MS (EI) t_(R) 1.79, m/z 286 (M⁺+1).

Procedure S.

Procedure S provides a method for the coupling between3-aminoquinuclidine and carboxaldehydes to form secondary aminederivatives.

The suspension of 1H-indazole-4-carboxaldehyde (100 mg),3-aminoquinuclidine dihydrocloride salt (1.0 eq), and 4 Å molecularsieves in dioxane (4 mL) was heated at reflux for 4 h. The reactionmixture was allowed to cool to rt and was treated with sodiumtriacetoxyborohydride (3 eq). The reaction mixture was maintained at rtfor 2 h and was poured into water, extracted with 5% methanol indichloromethane (2×30 mL), and the combined extracts were concentrated.The residue was purified by preparative HPLC.

The following compounds were prepared using this method:

Example 207N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(2-methoxyethyl)amino]-1H-indazole-3-carboxamidedihydroformate

Prepared using Procedure S in 48% yield. ¹H NMR (CD₃OD) δ 7.42 (d,J=9.0, 1H), 7.37 (s, 1H), 7.0 (d, J=9.0, 1H), 4.55 (m, 1H), 4.05 (m,1H), 3.85 (m, 2H), 3.61-3.50 (m, 8H), 3.35 (s, 3H), 2.49-3.0 (m, 2H),2.20 (m, 2H), 2.05 (m, 1H). LC/MS (EI) t_(R) 1.65, m/z 344 (M⁺+1).

Example 208N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylmethyl)amino]-1H-indazole-3-carboxamidedihydroformate

Prepared using Procedure S in 42% yield. LC/MS (EI) t_(R) 1.77, m/z 340(M⁺+1).

Example 209 Methyl4-[(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl)amino]butanoatedihydroformate

Prepared using Procedure S in 62% yield. LC/MS (EI) t_(R) 1.36, m/z 386(M⁺+1).

Example 210 Methyl4-[(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-6-yl)amino]butanoatedihydroformate

Prepared using Procedure S in 55% yield. LC/MS (EI) t_(R) 2.62, m/z 403(M⁺+1).

Example 211 tert-Butyl{2-[(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1,2-benzisothiazol-6-yl)amino]ethyl}propylcarbamatedihydroformate

Prepared using Procedure S in 63% yield. LC/MS (EI) t_(R) 5.59, m/z 488(M⁺+1).

Example 212N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(1,3-thiazol-2-ylmethyl)amino]-1H-indazole-3-carboxamidedihydroformate

Prepared using Procedure S in 30% yield. LC/MS (EI) t_(R) 2.84, m/z 383(M⁺+1).

Example 213N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(dimethylamino)-1H-indazole-3-carboxamidedihydroformate

Prepared using Procedure S in 52% yield. LC/MS (EI) t_(R) 1.68, m/z 314(M⁺+1).

Example 214N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2-methoxyethyl)-5-[(2-methoxyethyl)amino]-1H-indazole-3-carboxamidedihydroformate

Prepared using Procedure S in 9% yield. LC/MS (EI) t_(R) 2.84, m/z 402(M⁺+1).

Example 215N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[2-(diethylamino)-2-oxoethyl]amino}-1,2-benzisothiazole-3-carboxamidedihydroformate

Prepared using Procedure S in 67% yield. LC/MS (EI) t_(R) 3.67, m/z 416(M⁺+1).

Example 216N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(butylamino)-1H-indazole-3-carboxamidedihydroformate

Prepared using Procedure S in 47% yield. LC/MS (EI) t_(R) 2.38, m/z 342(M⁺+1).

Example 217N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylmethyl)amino]-1,2-benzisothiazole-3-carboxamidedihydroformate

Prepared using Procedure S in 45% yield. LC/MS (EI) t_(R) 4.50, m/z 357(M⁺+1).

Example 218N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(dimethylamino)-1,2-benzisothiazole-3-carboxamidedihydroformate

Prepared using Procedure S in 51% yield. LC/MS (EI) t_(R) 2.53, m/z 331(M⁺+1).

Example 219N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(diethylamino)-1,2-benzisothiazole-3-carboxamidedihydroformate

Prepared using Procedure S in 60% yield. LC/MS (EI) t_(R) 1.36, m/z 342(M⁺+1).

Procedure T.

Procedure T provides a method for the coupling between aminoaminoquinuclidinecarboxamides and acylating agents to form carboxamidederivatives.

To a solution of5-amino-N-[(3S)-1-azabicyclo[2,2,2]oct-3-yl]-1H-indazole-3-carboxamide(0.42 mmol) in pyridine (2 mL) and N,N-dimethylformamide (2 mL) wasadded the trifluoroacetic anhydride (0.55 mmol). The mixture wasmaintained at ambient temperature for 16 h and was concentrated invacuo. The residue was purified by preparative HPLC, thus providing theproduct in 30% yield and the bis-acylated product in 5% yield.

The following compounds were prepared by this method:

Example 220N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(4-methoxyphenyl)acetyl]amino}-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure T in 31% yield. ¹H NMR (CD₃OD) δ 8.52 (s, 1H),8.42 (s. 1H), 7.64-7.43 (m, 6H), 5.32 (s, 2H), 4.72 (m, 1H), 3.94 (m,1H), 3.70-3.40 (m, 4H), 2.51 (m, 1H), 2.50 (m, 1H), 2.20 (m, 2H), 2.06(m, 1H). LC/MS (EI) t_(R) 4.94, m/z 434 (M⁺+1).

Example 221N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1-(cyclopropylmethyl)-1H-indazole-3-carboxamide

Prepared using Procedure T in 45% yield. LC/MS (EI) t_(R) 4.77, m/z 408(M⁺+1).

Example 222N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(trifluoroacetyl)amino]-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure T in 30% yield. LC/MS (EI) t_(R) 3.28, m/z 382(M⁺+1).

Example 223N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure T in 30% yield. LC/MS (EI) t_(R) 2.61, m/z 354(M⁺+1).

Example 2245-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(trifluoroacetyl)-1H-indazole-3-carboxamidedihydroformate

Prepared using Procedure T in 30% yield. LC/MS (EI) t_(R) 2.92, m/z 382(M⁺+1).

Example 225N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylcarbonyl)-5-[(cyclopropylcarbonyl)amino]-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure T in 30% yield. LC/MS (EI) t_(R) 5.09, m/z 422(M⁺+1).

Example 226N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-[(4-methoxyphenyl)acetyl]-5-{[(4-methoxyphenyl)acetyl]amino}-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure T in 31% yield. LC/MS (EI) t_(R) 5.44, m/z 583(M⁺+1).

Example 227N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure T in 60% yield. LC/MS (EI) t_(R) 3.66, m/z 371(M⁺+1).

Example 2286-(Acetylamino)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure T in 60% yield. LC/MS (EI) t_(R) 2.42, m/z 345(M⁺+1).

Example 229N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1-ethyl-1H-indazole-3-carboxamide

Prepared using Procedure T in 33% yield. LC/MS (EI) t_(R) 3.44, m/z 382(M⁺+1).

Example 230N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1-cyclopropylmethyl-1H-indazole-3-carboxamide

Prepared using Procedure T in 44% yield. LC/MS (EI) t_(R) 3.68, m/z 408(M⁺+1).

Example 231N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxamide

Prepared using Procedure T in 47% yield. LC/MS (EI) t_(R) 3.66, m/z 436(M⁺+1).

Procedure U.

Procedure U provides a method for the coupling between aminoaminoquinuclidinecarboxamides and sulfonylating agents to formsulfonamide derivatives.

Ethanesulfonyl chloride (0.25 mmol.) was added to a solution of theamine (0.20 mmol) in a mixture of pyridine (2 mL) andN,N-dimethylformamide (1 mL). The mixture was maintained at ambienttemperature for 16 h and was concentrated in vacuo. The residue waspurified by preparative HPLC, thus providing the product in 60% yieldand the bis-sulfonylated product in 20% yield.

The following compounds were prepared by this method:

Example 232N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(ethylsulfonyl)amino]-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure U in 32% yield. ¹H NMR (CD₃OD) δ 8.09 (s, 1H),7.55 (d, J=8.9, 1H), 7.41 (d, J=8.9, 1H), 4.20 (m, 1H), 3.35 (m, 1H),3.08 (q, J=7.4, 2H), 3.02 (m, 1H), 3.0-2.8 (m, 4H), 2.06 (m, 1H), 2.00(m, 1H), 1.79 (m, 2H), 1.55 (m, 1H), 1.32 (t, J=7.4, 3H); LC/MS (EI)t_(R) 2.37, m/z 378 (M⁺+1).

Example 233N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(ethylsulfonyl)amino]-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure U in 74% yield. LC/MS (EI) t_(R) 2.85, m/z 395(M⁺+1).

Example 234N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(ethylsulfonyl)amino]-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure U in 73% yield. LC/MS (EI) t_(R) 2.82, m/z 395(M⁺+1).

Example 235N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(methylsulfonyl)amino]-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure U in 71% yield. LC/MS (EI) t_(R) 2.84, m/z 381(M⁺+1).

Example 236N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(methylsulfonyl)amino]-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure U in 69% yield. LC/MS (EI) t_(R) 2.82, m/z 381(M⁺+1).

Example 237N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(benzylsulfonyl)amino]-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure U in 35% yield. LC/MS (EI) t_(R) 4.64, m/z 440(M⁺+1).

Example 238N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(dimethylamino)sulfonyl]amino}-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure U in 48% yield. LC/MS (EI) t_(R) 3.53, m/z 410(M⁺+1).

Example 2395-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(benzylsulfonyl)-1H-indazole-3-carboxamidedihydroformate

Prepared using Procedure U in 35% yield. LC/MS (EI) t_(R) 4.29, m/z 440(M⁺+1).

Example 240N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(methylsulfonyl)amino]-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure U in 19% yield. LC/MS (EI) t_(R) 1.61, m/z 364(M⁺+1).

Example 241N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(ethylsulfonyl)amino]-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure U in 10% yield. LC/MS (EI) t_(R) 2.43, m/z 378(M⁺+1).

Example 242N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-[(methylsulfonyl)amino]-1H-indazole-3-carboxamide

Prepared using Procedure U in 9% yield. LC/MS (EI) t_(R) 3.96, m/z 364(M⁺+1).

Procedure V.

Procedure V provides a method for the coupling between aminoaminoquinuclidinecarboxamides and isocyanates to form urea derivatives.

To the amine (0.40 mmol) in a mixture of pyridine (2 mL) andN,N-dimethylformamide (1 mL) was added 5-chloro-2-methylphenylisocyanate (0.53 mmol). The reaction mixture was maintained at ambienttemperature for 16 h and was concentrated in vacuo. The residue waspurified by chromatography (70/30/1 ethyl acetate/methanol/ammoniumhydroxide), thus providing the product in 78% yield.

The following compounds were prepared by this method:

Example 243N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(2,6-dichlorophenyl)ethyl]amino}carbonyl)amino]-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure V in 70% yield. ¹H NMR (CD₃OD) δ 8.68 (d,J=9.0, 1H), 8.46 (s, 1H), 7.47-7.30 (m, 3H), 7.33 (d, J=9.0, 1H), 3.97(m, 1H), 3.96 (t, J=12.0, 1H), 3.64 (t, J=6.0, 2H), 3.50-3.30 (m, 6H),2.52 (m, 1H), 2.40 (m, 1H), 2.20 (m, 2H), 2.10 (m, 1H). LC/MS (EI) t_(R)5.55, m/z 518 (M⁺+1).

Example 244N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-6-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamide

Prepared using Procedure V in 32% yield. LC/MS (EI) t_(R) 4.88, m/z 425(M⁺+1).

Example 245N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3-cyanophenyl)amino]carbonyl}-amino)-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure V in 40% yield. LC/MS (EI) t_(R) 5.74, m/z 447(M⁺+1).

Example 246N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(4-fluorophenyl)ethyl]amino}carbonyl)amino]-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure V in 50% yield. LC/MS (EI) t_(R) 5.42, m/z 454(M⁺+1).

Example 247N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3,4-dimethylphenyl)amino]carbonyl}amino)-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure V in 76% yield. LC/MS (EI) t_(R) 5.79, m/z 450(M⁺+1).

Example 248N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2,5-dimethylphenyl)amino]carbonyl}amino)-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure V in 78% yield. LC/MS (EI) t_(R) 5.92, m/z 470(M⁺+1).

Example 249N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-methylbenzyl)amino]carbonyl}amino)-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure V in 40% yield. LC/MS (EI) t_(R) 5.78, m/z 450(M⁺+1).

Example 250N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(4-methylphenyl)ethyl]amino}carbonyl)amino]-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure V in 71% yield. LC/MS (EI) t_(R) 5.54, m/z 450(M⁺+1).

Example 251N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(3-methoxyphenyl)ethyl]amino}carbonyl)amino]-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure V in 74% yield. LC/MS (EI) t_(R) 5.37, m/z 466(M⁺+1).

Example 252N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(cyclopentylamino)carbonyl]amino}-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure V in 63% yield. LC/MS (EI) t_(R) 5.34, m/z 414(M⁺+1).

Example 253N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(propylamino)carbonyl]amino}-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure V in 70% yield. LC/MS (EI) t_(R) 4.40, m/z 388(M⁺+1).

Example 254N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-3-carboxamide

Prepared using Procedure V in 65% yield. LC/MS (EI) t_(R) 5.03, m/z 397(M⁺+1).

Example 255N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(3-methoxybenzyl)amino]carbonyl}amino)-1H-indazole-3-carboxamide

Prepared using Procedure V in 68% yield. LC/MS (EI) t_(R) 5.02, m/z 449(M⁺+1).

Example 256N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(cyclopentylamino)carbonyl]amino}-1H-indazole-3-carboxamide

Prepared using Procedure V in 54% yield. LC/MS (EI) t_(R) 4.24, m/z 397(M⁺+1).

Example 257N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(3-methoxybenzyl)amino]carbonyl}amino)-1H-indazole-3-carboxamide

Prepared using Procedure V in 64% yield. LC/MS (EI) t_(R) 4.75, m/z 434(M⁺+1).

Example 258N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-3-carboxamide

Prepared using Procedure V in 57% yield. LC/MS (EI) t_(R) 5.03, m/z 397(M⁺+1).

Example 259N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(propylamino)carbonyl]amino}-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure V in 70% yield. LC/MS (EI) t_(R) 4.78, m/z 388(M⁺+1).

Example 260N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure V in 35% yield. LC/MS (EI) t_(R) 2.87, m/z 371(M⁺+1).

Example 261N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure V in 30% yield. LC/MS (EI) t_(R) 2.91, m/z 371(M⁺+1).

Example 262N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure V in 41% yield. LC/MS (EI) t_(R) 5.03, m/z 397(M⁺+1).

Example 263N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure V in 36% yield. LC/MS (EI) t_(R) 5.02, m/z 437(M⁺+1).

Example 264N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(cyclopentylamino)carbonyl]amino}-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure V in 34% yield. LC/MS (EI) t_(R) 4.24, m/z 397(M⁺+1).

Example 265N(3)-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-(3-methoxybenzyl)-5-({[(3-methoxybenzyl)amino]carbonyl}amino)-1H-indazole-1,3-dicarboxamide

Prepared using Procedure V in 14% yield. LC/MS (EI) t_(R) 5.74, m/z 612(M⁺+1).

Example 266N(3)-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-(4-fluorobenzyl)-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-1,3-dicarboxamide

Prepared using Procedure V in 13% yield. LC/MS (EI) t_(R) 5.81, m/z 588(M⁺+1).

Example 267N(3)-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-cyclopentyl-5-{[(cyclopentylamino)carbonyl]amino}-1H-indazole-1,3-dicarboxamidehydroformate

Prepared using Procedure V in 13% yield. LC/MS (EI) t_(R) 5.51, m/z 508(M⁺+1).

Example 268N(3)[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-propyl-5-{[(propylamino)carbonyl]amino}-1H-indazole-1,3-dicarboxamide

Prepared using Procedure V in 9.4% yield. LC/MS (EI) t_(R) 5.24, m/z 456(M⁺+1).

Example 269N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(cyclopropylmethyl)amino]carbonothioyl}amino)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure V in 47% yield. LC/MS (EI) t_(R) 2.75, m/z 399(M⁺+1).

Example 270N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(cyclopropylmethyl)amino]carbonothioyl}amino)-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure V in 26% yield. LC/MS (EI) t_(R) 3.98, m/z 416(M⁺+1).

Example 271N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(propylmethylamino)carbonothioyl]amino}-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure V in 60% yield. LC/MS (EI) t_(R) 3.01, m/z 404(M⁺+1).

Example 272N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(tert-butylamino)carbonothioyl]amino}-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure V in 47% yield. LC/MS (EI) t_(R) 3.65, m/z 385(M⁺+1).

Example 273N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(sec-butylamino)carbonyl]amino}-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure V in 43% yield. LC/MS (EI) t_(R) 2.46, m/z 385(M⁺+1).

Example 274N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure V in 11% yield. LC/MS (EI) t_(R) 3.50, m/z 399(M⁺+1).

Example 275N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-5-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure V in 56% yield. LC/MS (EI) t_(R) 3.74, m/z 425(M⁺+1).

Example 276N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethyl)-5-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure V in 40% yield. LC/MS (EI) t_(R) 3.72, m/z 453(M⁺+1).

Example 277N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-5-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure V in 37% yield. LC/MS (EI) t_(R) 3.44, m/z 399(M⁺+1).

Procedure W

Procedure W provides a method for the coupling between aminoaminoquinuclidinecarboxamides and halogenated heterocycles to formN-heteroarylaniline derivatives.

To a solution of6-amino-N-[(3S)-1-azabicyclo[2.2.2]octy-3-yl]-1,2-benisothiazole-3-carboxamide(0.175 mmol) in a mixture of toluene (0.5 mL) and 2-propanol (0.5 mL)was added 2-bromothiazole (0.18 mmol) an potassium carbonate (0.21mmol). The reaction mixture was subjected to microwave irradiation at180° C. for 600 s, and was concentrated. The residue was resuspended in95/5 dichloromethane/methanol and was filtered and concentrated. Theresidue was purified by preparative HPLC, thus providing the product in10% yield.

The following compounds were prepared using this method:

Example 278N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-ylamino)-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure W in 10% yield. LC/MS (EI) t_(R) 4.78, m/z 386(M⁺+1).

Procedure X

Procedure X provides a method for the coupling between acetylenicaminoquinuclidinecarboxamides and azides to form triazole derivatives.

N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide(0.300 mol) and azidotrimethylsilane (0.30 mmol) were suspended in water(0.6 mL) and tert-butyl alcohol (0.6 mL). Sodium ascorbate (0.20 mol)was added to the reaction mixture followed by a solution ofcopper(II)sulfate pentahydrate (0.030 mmol) in water (30 μL). Thereaction was stirred vigorously for 12 hours, and was concentrated. Theresidue was redissolved in methanol and was filtered and concentrated.The residue was purified by preparative HPLC, thus providing the productin 6% yield.

The following compounds were prepared by this method:

Example 279N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1H-1,2,3-triazol-4-yl)-1H-indazole-3-carboxamidedihydroformate

Prepared using Procedure X in 6% yield. ¹H NMR (CD₃OD) δ 8.69 (s, 1H),8.27 (s, 1H), 7.97 (d, 1H, J=8.8), 7.72 (d, J=8.8), 4.58-4.43 (m, 1,3.91-3.84 (m, 1, 3.49-3.38 (m, 4, 2.43-1.97 (m, 6. LC/MS (EI) t_(R)2.77, m/z 338 (M⁺+1).

Example 280N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[1-(2-piperidin-1-ylethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole-3-carboxamidedihydroformate

Prepared using Procedure X in 55% yield. LC/MS (EI) t_(R) 2.04, m/z 449(M⁺+1).

Example 281Ethyl[4-(3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-6-yl)-1H-1,2,3-triazol-1-yl]acetatedihydroformate

Prepared using Procedure X in 20% yield. LC/MS (EI) t_(R) 3.15, m/z 424(M⁺+1).

Procedure Y.

Procedure Y provides a method for the coupling between aminoaminoquinuclidinecarboxamides and chloroformates to form carbamatederivatives.

Benzyl chloroformate (0.58 mmol.) was added to a solution of the amine(0.52 mmol) in N,N-dimethylformamide (1 mL) and pyridine (2 mL) and thereaction mixture was maintained for 16 h. The reaction mixture wasconcentrated and the residue was purified by preparative HPLC, thusproviding the product in 54% yield and the bis-carbamate in 12% yield.

The following compounds were prepared by this method:

Example 282Benzyl(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl)carbamate

Prepared using Procedure Y in 54% yield. ¹H NMR (CD₃OD) δ 8.59 (s, 1H),8.51 (s, 1H), 7.65 (s, 1H), 7.41 (d, J=9.0, 1H), 7.19 (d, J=9.0, 1H),7.05 (d, J=9.0, 1H), 7.05 (d, J=9.0, 1H), 6.94 (d, J=9.0, 1H), 4.62 (m,1H), 3.95 (m, 1H), 3.87 (s, 3H), 3.50-3.30 (m, 4H), 2.48 (m, 1H), 2.37(m, 1H), 2.20 (m, 2H), 2.02 (m, 1H). LC/MS (EI) t_(R) 5.33, m/z 420(M⁺+1).

Example 283Vinyl(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl)carbamate

Prepared using Procedure Y in 50% yield. LC/MS (EI) t_(R) 3.30, m/z 356(M⁺+1).

Example 284Isopropyl{3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl}carbamatehydroformate

Prepared using Procedure Y in 36% yield. LC/MS (EI) t_(R) 2.90, m/z 372(M⁺+1).

Example 285Isopropyl{3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-[(isopropylamino)carbonyl]-1H-indazol-5-yl}carbamatehydroformate

Prepared using Procedure Y in 18% yield. LC/MS (EI) t_(R) 5.16, m/z 458(M⁺+1).

Procedure Z.

Procedure Z provides a method for the oxidation ofquinuclidinecarboxamides to form N-oxide derivatives.

A 0° C. solution of m-chloroperbenzoic acid (6.66 mmol.) indichloromethane (30 mL) was added dropwise to a solution of thequinuclidine amide (4.44 mmol) in dichloromethane (40 mL) and thereaction mixture was maintained for 3 h. The reaction mixture wasconcentrated and the residue was purified by chromatography on neutralalumina using a gradient of 100/0 to 90/10 dichloromethane/methanol,thus providing the product in 58% yield.

The following compounds were prepared by this method:

Example 286N-[(3S)-1-Oxido-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide

Prepared using Procedure Z in 58% yield. ¹H NMR (CD₃OD, 500 MHz) δ 8.21(d, J=8.0, 1H), 7.59 (d, J=9.0, 1H), 7.42 (dt, Jt=7.5, Jd=1.0, 1H), 7.26(dt, Jt=7.5, Jd=1.0, 1H), 4.65 (m, 1H), 3.83 (m, 1H), 3.42 (m, 5H), 2.37(m, 4H), 2.27 (m, 1H), 2.17 (m, 2H), 2.02 (m, 1H); LC/MS (EI) t_(R) 12.4[Analytical HPLC was performed on 4.6 mm×250 mm YMC 0DS-AQ S-5 120 mcolumns using a gradient of 05/95 to 95/05 acetonitrile (0.05%trifluoroacetic acid)/water (0.05% trifluoroacetic acid) over 35 min],m/z 287 (M⁺+1).

Procedure AA.

Procedure AA provides a method for the demethylation ofmethoxy-substituted quinuclidinecarboxamides to form phenol derivatives.

The following compounds were prepared by this method:

Example 287N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1H-indazole-3-carboxamidehydrobromide

Prepared using Procedure AA in 32% yield. ¹H NMR (Me₂SO-d₆) δ 13.43 (s,1H), 9.49 (br s, 1H), 9.35 (s, 1H), 8.62 (d, J=5.9, 1H), 7.46-7.44 (m,1H), 6.95 (d, J=6.5, 1H), 4.41 (br s, 1H), 3.68-3.63 (m, 1H), 3.33-3.18(m, 7H), 2.22-2.20 (m, 1H), 2.09-2.08 (m, 1H), 1.94-1.93 (m, 1H),1.75-1.70 (M, 1H). LC/MS (EI) t_(R) 10.72, m/z 287 (M⁺+1).

Example 288N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamidehydrobromide

Prepared using Procedure AA in 39% yield. LC/MS (EI) t_(R) 10.32[Analytical HPLC was performed on 4.6 mm×250 mm YMC 0DS-AQ S-5 120 mcolumns using a gradient of 05/95 to 95/05 acetonitrile (0.05%trifluoroacetic acid)/water (0.05% trifluoroacetic acid) over 35 min],m/z 287 (M⁺+1).

Procedure AB.

Procedure AB provides a method for the preparation of urea derivativesusing phosgene equivalents.

The following compounds were prepared by this method:

Example 289N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(diethylamino)carbonyl]amino}-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure AB in 55% yield. ¹H NMR (CD₃OD) δ 8.40 (s, 1H),8.10 (s, 1H), 7.51 (s, 1H), 4.52 (m, 1H), 3.83 (t, J=15.0, 1H), 3.37 (t,J=9.0, 4H), 3.36-3.30 (m, 4H), 2.30 (m, 1H), 2.15 (m, 2H), 1.95 (m, 1H),1.19 (t, J=6.0, 6H). LC/MS (EI) t_(R) 2.45, m/z 385 (M⁺+1).

Example 290N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(pyrrolidin-1-ylcarbonyl)amino]-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure AB in 57% yield. LC/MS (EI) t_(R) 2.47, m/z 383(M⁺+1).

Example 291N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(pyrrolidin-1-ylcarbonyl)amino]-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure AB in 69% yield. LC/MS (EI) t_(R) 3.35, m/z 400(M⁺+1).

Procedure AC.

Procedure AC provides a method for the preparation of cyclic amidederivatives from the corresponding brominated quinuclidine derivatives.Palladium (II) acetate (0.09 mmol) was added to a solution of(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.14 mmol) intoluene (10 mL) and the reaction mixture was maintained until thecontents completely dissolved. The resultant yellow solution wastransferred to a mixture ofN-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisothiazole-3-carboxamide(0.33 mmol), cesium carbonate (0.60 mmol) and 2-pyrrolidinone (1.00mmol) under an atmosphere of nitrogen gas and the reaction mixture washeated at 100° C. for 16 h. The reaction mixture was filtered throughCelite and concentrated. The residue was purified by HPLC, thusproviding the product in 72% yield.

The following compounds were prepared using this method:

Example 292N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxopyrrolidin-1-yl)-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure AC in 72% yield. ¹H NMR (CD₃OD) δ 8.78 (d,J=9.0, 1H), 8.53 (broad, 1H), 8.81 (s, 1H), 7.63 (d, J=9.0, 1H), 4.5 (m,1H), 4.07 (t, J=6.0, 2H), 3.76 (t, J=12.0, 1H), 3.50-3.30 (m, 4H), 2.35(t, J=6.0, 2H), 2.35 (m, 1H), 2.20 (m, 3H), 2.10 (m, 2H), 1.90 (m, 1H).LC/MS (EI) t_(R) 2.43, m/z 371 (M⁺+1).

Example 293N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-oxopyrrolidin-1-yl)-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure AC in 40% yield. LC/MS (EI) t_(R) 2.11, m/z 354(M⁺+1).

Example 294N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxo-4-phenylpyrrolidin-1-yl)-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure AC in 50% yield. LC/MS (EI) t_(R) 5.17, m/z 447(M⁺+1).

Procedure AD.

Procedure AD provides a method for the preparation of cyclic ureaderivatives from the corresponding amino quinuclidine derivatives.

To a solution of6-amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide(0.400 mmol) in methanol (5 mL) was added tert-butylN-(2-oxoethyl)carbamate (0.56 mmol), sodium cyanoborohydride (1.00 mmol)and acetic acid (0.4 mL) and the reaction mixture was maintained for 4h. The reaction mixture was diluted with 3 N hydrochloric acid (5 mL)and the reaction mixture was maintained for 2 h. The reaction mixturewas concentrated and the residue was purified by HPLC, thus providingthe reduced amine in 63% yield.

To solution of the reduced amine (0.100 mmol) in N,N-dimethylformamide(4 mL) was added N,N-carbonyldiimidazole (0.150 mmol) and the reactionmixture was heated at 100° C. for 3 h. The reaction mixture wasconcentrated and the residue was purified by HPLC, thus providing thecyclic urea in 60% yield.

The following compounds were prepared using this method:

Example 295N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxoimidazolidin-1-yl)-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure AD in 60% yield. ¹H NMR (CD₃OD) δ 8.67 (d,J=9.0, 1H), 8.51 (broad, 1H), 8.18 (s, 1H), 7.96 (d, J=9.0, 1H), 4.48(d, 1H), 4.08 (dd, J=6.0, 6.0, 2H), 3.79 (t, J=12.0, 1H), 3.60 (dd,J=6.0, 6.0, 2H), 3.5-3.3 (m, 4H), 2.38 (m, 1H), 2.22 (m, 1H), 2.08 (m,2H), 1.90 (m, 1H). LC/MS (EI) t_(R) 2.43, m/z 372 (M⁺+1).

Example 296N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-oxoimidazolidin-1-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure AD in 60% yield. LC/MS (EI) t_(R) 1.26, m/z 355(M⁺+1).

Example 297N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-oxo-3-propylimidazolidin-1-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure AD in 40% yield. LC/MS (EI) t_(R) 3.27, m/z 397(M⁺+1).

Example 298N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[2-(propylamino)ethyl]amino}-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure AD in 35% yield. LC/MS (EI) t_(R) 1.47, m/z 303(M⁺+1).

Procedure AE.

Procedure AE provides a method for the preparation of cyclic ureaderivatives from the corresponding brominated quinuclidine derivatives.

Palladium (II) acetate (0.09 mmol) was added to a solution of(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.14 mmol) intoluene (8 mL) and the reaction mixture was maintained until thecontents completely dissolved. The resultant yellow solution wastransferred to a mixture ofN-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisothiazole-3-carboxamide(0.33 mmol), cesium carbonate (0.39 mmol) and 1-methyl-2-imidazolidinone2-pyrrolidinone (0.500 mmol) under an atmosphere of nitrogen gas and thereaction mixture was heated at 100° C. for 16 h. The reaction mixturewas filtered through Celite and concentrated. The residue was purifiedby HPLC, thus providing the product in 70% yield.

The following compounds were prepared using this method:

Example 299N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methyl-2-oxoimidazolidin-1-yl)-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure AE in 70% yield. ¹H NMR (CD₃OD) δ 8.64 (d,J=9.0, 1H), 8.55 (s, 1H), 8.18 (d, J=9.0, 1H), 4.20 (m, 1H), 3.95 (dd,J=6.0, 6.0, 2H), 3.51 (dd, J=6.0, 6.0, 2H), 3.35 (s, 3H), 3.45-3.30 (m,4H), 2.10 (m, 1H), 1.95 (m, 1H), 1.80 (m, 2H), 1.60 (m, 1H). LC/MS (EI)t_(R) 2.73, m/z 386 (M⁺+1).

Example 300N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-isopropyl-2-oxoimidazolidin-1-yl)-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure AE in 65% yield. LC/MS (EI) t_(R) 3.65, m/z 414(M⁺+1).

Example 301N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-propyl-2-oxoimidazolidin-1-yl)-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure AE in 67% yield. LC/MS (EI) t_(R) 4.61, m/z 414(M⁺+1).

Example 302N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-methyl-2-oxoimidazolidin-1-yl)-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure AF in 27% yield. LC/MS (EI) t_(R) 3.07, m/z 387(M⁺+1).

Example 303N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-isopropyl-2-oxoimidazolidin-1-yl)-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure AF in 31% yield. LC/MS (EI) t_(R) 3.70, m/z 414(M⁺+1).

Example 304N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-propyl-2-oxoimidazolidin-1-yl)-1,2-benzisothiazole-3-carboxamide

Prepared using Procedure AF in 24% yield. LC/MS (EI) t_(R) 3.66, m/z 414(M⁺+1).

Procedure AF.

Procedure AF provides a method for the preparation of benzisoxazolequinuclidine amides from ethyl benzisoxazole-3-carboxylates.

(S)-3-aminoquinuclidine hydrochloride (3.52 mmol) was dissolved inN,N-diisopropylethylamine (0.5 mL) and ethanol (3 mL) with warming.Ethyl 5-bromo-1,2-benzisoxazole-3-carboxylate (1.86 mmol) was added andthe reaction mixture was heated at 85° C. for 72 h. The reaction mixturewas diluted with dichloromethane (30 mL) and washed with 10 mL ofsaturated sodium carbonate. The aqueous layer was extracted withdichloromethane (30 mL) and the combined organic layers were washed withbrine and dried (sodium sulfate). The organic layer was loaded on a 10 gSCX column and the column was washed with methanol (50 mL). The crudeproduct was eluted with 2 M ammonia in methanol (60 mL) andconcentrated. The residue was purified by chromatography [40/60 to 0/100ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)], thusproviding the amide in 59% yield as a light yellow oil.

The following compounds were prepared using this method:

Example 305N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1,2-benzisoxazole-3-carboxamide

Prepared using Procedure AF in 59% yield. ¹H NMR (CD₃OD) δ 8.16 (d,J=0.6, 1H), 7.71 (dd, J=8.9, 0.6, 1H), 7.59 (d, J=8.9, 1H), 4.21 (m,1H), 3.37 (m, 1H), 3.02 (m, 1H), 2.84 (m, 4H), 2.08 (m, 1H), 1.96 (m,1H), 1.78 (m, 2H), 1.55 (m, 1H); LC/MS (EI) t_(R) 2.33, m/z 350/352(M+/M++2).

Example 306N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisoxazole-3-carboxamide

Prepared using Procedure AF in 63% yield. LC/MS (EI) t_(R) 2.22, m/z350/352 (M⁺+1).

Procedure AG.

Procedure AG provides a method for the preparation of acyclic amidederivatives from the corresponding brominated quinuclidine derivatives.

Palladium (II) acetate (0.040 mmol) was added to a solution of(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.050 mmol) intoluene (6 mL) and the reaction mixture was maintained until thecontents completely dissolved. The resultant yellow solution wastransferred to a mixture ofN-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisothiazole-3-carboxamide(0.30 mmol), cesium carbonate (0.50 mmol) and N-methylacetamide (0.500mmol) under an atmosphere of nitrogen gas and the reaction mixture wassubjected to microwave irradiation at 200° C. for 300 s. The reactionmixture was filtered through Celite and concentrated. The residue waspurified by HPLC, thus providing the product in 50% yield.

The following compounds were prepared using this method:

Example 3076-[Acetylmethyl)amino]-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure AG in 50% yield. ¹H NMR (CD₃OD) δ 8.85 (d,J=9.0, 2H), 8.40 (broad, 1H), 8.13 (s, 1H), 7.53 (d, J=9.0, 1H), 4.43(m, 1H), 3.85 (m, 1H), 3.5-3.2 (m, 7H), 2.45 (m, 1H), 2.30 (m, 1H), 2.10(m, 3H), 1.95 (m, 3H). LC/MS (EI) t_(R) 2.40, m/z 359 (M⁺+1).

Example 308N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[methyl(propionyl)amino]-1,2-benzisothiazole-3-carboxamidehydroformate

Prepared using Procedure AG in 60% yield. LC/MS (EI) t_(R) 2.42, m/z 373(M⁺+1).

Example 309N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure AH in 31% yield. ¹H NMR (CD₃OD) δ 8.43 (s, 1H),8.28 (d, J=8.4, 1H), 8.27 (s, 1H), 7.94 (d, J=3.3, 1H), 7.85 (d, J=8.3,1H), 7.68 (d, J=3.3, 1H), 4.55 (m, 1H), 4.46 (d, J=7.0, 2H), 3.84 (m,1H), 3.6-3.3 (m, 5H), 2.41 (m, 1H), 2.29 (m, 1H), 2.15 (m, 2H), 1.95 (m,1H), 1.45 (m, 1H), 0.62 (m, 2H), 0.53 (m, 2H); LC/MS (EI) t_(R) 3.99min, m/z 408 (M⁺+1).

Example 310N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(tetrahydrofuran-3-yl)-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure AH in 40% yield. LC/MS (EI) t_(R) 3.68 min, m/z424 (M⁺+1).

Example 311N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2-methoxyethyl)-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure AH in 27% yield. LC/MS (EI) t_(R) 3.64 min, m/z412 (M⁺+1).

Example 312 tert-Butyl3-[3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-6-(1,3-thiazol-2-yl)-1H-indazol-1-yl]pyrrolidine-1-carboxylatehydroformate

Prepared using Procedure AH in 38% yield. LC/MS (EI) t_(R) 4.30 min, m/z523 (M⁺+1).

Example 313N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-pyrrolidin-3-yl-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide

Prepared from Example 312, by exposure to trifluoroacetic acid, in 88%yield. LC/MS (EI) t_(R) 2.41 min, m/z 423 (M⁺+1).

Example 314N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1-(2-thienylmethyl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure AH in 11% yield. LC/MS (EI) t_(R) 4.15 min, m/z450 (M⁺+1).

Example 315N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2-phenoxyethyl)-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate

Prepared using Procedure AH in 54% yield. LC/MS (EI) t_(R) 4.33 min, m/z474 (M⁺+1).

Example 316 [³H] MLA Binding Materials:

Rat Brain: Pel-Freez Biologicals, CAT No. 56004-2

Protease inhibitor cocktail tablet: Roche, CAT No. 1697498

Membrane Preparation

Rat brains in 20 vol (w/v) of ice-cold 0.32 M sucrose with proteaseinhibitors (one tablet per 50 ml,) were homogenized with a polytron for10 sec at setting 11, then centrifuged 10 min at 1000 g, 4° C. Thesupernatant was centrifuged again for 20 min at 20,000 g, 4° C. Thepellets were resuspended in binding buffer (200 mM TRIS-HCl, 20 mMHEPES, pH 7.5, 144 mM NaCl, 1.5 mM KCl, 1 mM MgSO₄, 2 mM CaCl₂, 0.1%(w/v) BSA) and stored membrane prep at −80° C.

For saturation assay, the 200 μl assay mixture in binding buffercontains 200 μg of membrane protein, 0.2 to 44 nM of [³H] MLA. Thenonspecific binding was defined using 1 μM MLA. Competition assay wascarried out with 2 nM [³H] MLA and a desirable range of compounds. Theassay mixture was incubated at 22° C. for 2 hours, then harvested withGF/B filter presoaked with 0.3% PEI in binding buffer using Tomtecharvester. The filter was washed three time with binding buffer and theradioactivity was counted with Trilux.

Binding affinities for the preferred compounds of the invention are 2 nMto 25 μM, especially 2 nM to 2.5 μM.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

While the invention has been illustrated with respect to the productionand of particular compounds, it is apparent that variations andmodifications of the invention can be made without departing from thespirit or scope of the invention.

1-47. (canceled)
 48. A method of treating a patient suffering from apsychotic disease, a neurodegenerative disease involving a dysfunctionof the cholinergic system, and/or a condition of memory and/or cognitionimpairment, comprising administering to the patient an effective amountof a compound according to Formula I or Formula II:

wherein A is

X is O or S; R′ is H; R¹ is OH, CN, nitro, NH₂, alkyl having 1 to 4carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, alkenylhaving 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, whereinthe alkyl, fluorinated alkyl, alkenyl, or alkynyl groups are in eachunsubstituted or substituted by Ar or Het, alkoxy having 1 to 4 carbonatoms, cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4to 7 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms,fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxyhaving 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylaminowherein each alkyl group independently has 1 to 4 carbon atoms, Het, orOAr; R² is H, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms; Ar isphenyl which is unsubstituted or substituted one or more times by alkylhaving 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, halogen,dialkylamino wherein the alkyl portions each have 1 to 8 C atoms, amino,cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 C atoms,halogenated alkoxy having 1 to 8 C atoms, hydroxyalkyl having 1 to 8 Catoms, hydroxyalkoxy having 2 to 8 C atoms, alkenyloxy having 3 to 8 Catoms, alkylthio having 1 to 8 C atoms, alkylsulphinyl having 1 to 8 Catoms, alkylsulphonyl having 1 to 8 C atoms, monoalkylamino having 1 to8 C atoms, cycloalkylamino wherein the cycloalkyl group has 3 to 7 Catoms and is optionally substituted, aryloxy wherein the aryl portioncontains 6 to 10 carbon atoms and is optionally substituted, arylthiowherein the aryl portion contains 6 to 10 carbon atoms and is optionallysubstituted, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 Catoms and is optionally substituted, sulfo, sulfonylamino, acylamido,acyloxy or combinations thereof; Het is dihydropyranyl,tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, oxazolyl, pyrrolidinyl,piperidinyl, imidazolyl, imidazolidinyl, or morpholinyl, which isunsubstituted or substituted one or more times by alkyl having 1 to 8 Catoms, alkoxy having 1 to 8 C atoms; or a pharmaceutically acceptablesalt thereof, wherein A is attached to the remainder of the compound viaits 3 position.
 49. A method according to claim 48, wherein said patientis suffering from schizophrenia, anxiety, mania, depression, manicdepression, Tourette's syndrome, Parkinson's disease, Huntington'sdisease, Alzheimer's disease, Lewy Body Dementia, Amyotrophic LateralSclerosis, memory impairment, memory loss, cognition deficit, attentiondeficit, and/or Attention Deficit Hyperactivity Disorder.
 50. A methodof treating a patient suffering from dementia and/or another conditionwith memory loss, comprising administering to the patient an effectiveamount of a compound according to Formula I or Formula II:

wherein A is

X is O or S; R′ is H; R¹ is OH, CN, nitro, NH₂, alkyl having 1 to 4carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, alkenylhaving 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, whereinthe alkyl, fluorinated alkyl, alkenyl, or alkynyl groups are in eachunsubstituted or substituted by Ar or Het, alkoxy having 1 to 4 carbonatoms, cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4to 7 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms,fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxyhaving 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylaminowherein each alkyl group independently has 1 to 4 carbon atoms, Het, orOAr; R² is H, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms; Ar isphenyl which is unsubstituted or substituted one or more times by alkylhaving 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, halogen,dialkylamino wherein the alkyl portions each have 1 to 8 C atoms, amino,cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 C atoms,halogenated alkoxy having 1 to 8 C atoms, hydroxyalkyl having 1 to 8 Catoms, hydroxyalkoxy having 2 to 8 C atoms, alkenyloxy having 3 to 8 Catoms, alkylthio having 1 to 8 C atoms, alkylsulphinyl having 1 to 8 Catoms, alkylsulphonyl having 1 to 8 C atoms, monoalkylamino having 1 to8 C atoms, cycloalkylamino wherein the cycloalkyl group has 3 to 7 Catoms and is optionally substituted, aryloxy wherein the aryl portioncontains 6 to 10 carbon atoms and is optionally substituted, arylthiowherein the aryl portion contains 6 to 10 carbon atoms and is optionallysubstituted, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 Catoms and is optionally substituted, sulfo, sulfonylamino, acylamido,acyloxy or combinations thereof; Het is dihydropyranyl,tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, oxazolyl, pyrrolidinyl,piperidinyl, imidazolyl, imidazolidinyl, or morpholinyl, which isunsubstituted or substituted one or more times by alkyl having 1 to 8 Catoms, alkoxy having 1 to 8 C atoms; or a pharmaceutically acceptablesalt thereof, wherein A is attached to the remainder of the compound viaits 3 position.
 51. A method of treating a patient suffering from memoryimpairment due to Alzheimer's disease, mild cognitive impairment due toaging, schizophrenia, Parkinson's disease, Huntington's disease, Pick'sdisease, Creutzfeldt-Jakob disease, depression, aging, head trauma,stroke, CNS hypoxia, cerebral senility, multiinfarct dementia, HIVand/or cardiovascular disease comprising administering to the patient aneffective amount of a compound according to Formula I or Formula II:

wherein A is

X is O or S; R′ is H; R¹ is OH, CN, nitro, NH₂, alkyl having 1 to 4carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, alkenylhaving 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, whereinthe alkyl, fluorinated alkyl, alkenyl, or alkynyl groups are in eachunsubstituted or substituted by Ar or Het, alkoxy having 1 to 4 carbonatoms, cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4to 7 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms,fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxyhaving 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylaminowherein each alkyl group independently has 1 to 4 carbon atoms, Het, orOAr; R² is H, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms; Ar isphenyl which is unsubstituted or substituted one or more times by alkylhaving 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, halogen,dialkylamino wherein the alkyl portions each have 1 to 8 C atoms, amino,cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 C atoms,halogenated alkoxy having 1 to 8 C atoms, hydroxyalkyl having 1 to 8 Catoms, hydroxyalkoxy having 2 to 8 C atoms, alkenyloxy having 3 to 8 Catoms, alkylthio having 1 to 8 C atoms, alkylsulphinyl having 1 to 8 Catoms, alkylsulphonyl having 1 to 8 C atoms, monoalkylamino having 1 to8 C atoms, cycloalkylamino wherein the cycloalkyl group has 3 to 7 Catoms and is optionally substituted, aryloxy wherein the aryl portioncontains 6 to 10 carbon atoms and is optionally substituted, arylthiowherein the aryl portion contains 6 to 10 carbon atoms and is optionallysubstituted, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 Catoms and is optionally substituted, sulfo, sulfonylamino, acylamido,acyloxy or combinations thereof; Het is dihydropyranyl,tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, oxazolyl, pyrrolidinyl,piperidinyl, imidazolyl, imidazolidinyl, or morpholinyl, which isunsubstituted or substituted one or more times by alkyl having 1 to 8 Catoms, alkoxy having 1 to 8 C atoms; or a pharmaceutically acceptablesalt thereof, wherein A is attached to the remainder of the compound viaits 3 position.
 52. (canceled)
 53. (canceled)
 54. (canceled) 55.(canceled)
 56. (canceled)
 57. (canceled)
 58. A method for treating lossof memory comprising administering to a patient in need thereof aneffective amount of a compound according to Formula I or Formula II:

wherein A is

X is O or S; R′ is H; R¹ is OH, CN, nitro, NH₂, alkyl having 1 to 4carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, alkenylhaving 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, whereinthe alkyl, fluorinated alkyl, alkenyl, or alkynyl groups are in eachunsubstituted or substituted by Ar or Het, alkoxy having 1 to 4 carbonatoms, cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4to 7 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms,fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxyhaving 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylaminowherein each alkyl group independently has 1 to 4 carbon atoms, Het, orOAr; R² is H, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms; Ar isphenyl which is unsubstituted or substituted one or more times by alkylhaving 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, halogen,dialkylamino wherein the alkyl portions each have 1 to 8 C atoms, amino,cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 C atoms,halogenated alkoxy having 1 to 8 C atoms, hydroxyalkyl having 1 to 8 Catoms, hydroxyalkoxy having 2 to 8 C atoms, alkenyloxy having 3 to 8 Catoms, alkylthio having 1 to 8 C atoms, alkylsulphinyl having 1 to 8 Catoms, alkylsulphonyl having 1 to 8 C atoms, monoalkylamino having 1 to8 C atoms, cycloalkylamino wherein the cycloalkyl group has 3 to 7 Catoms and is optionally substituted, aryloxy wherein the aryl portioncontains 6 to 10 carbon atoms and is optionally substituted, arylthiowherein the aryl portion contains 6 to 10 carbon atoms and is optionallysubstituted, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 Catoms and is optionally substituted, sulfo, sulfonylamino, acylamido,acyloxy or combinations thereof; Het is dihydropyranyl,tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, oxazolyl, pyrrolidinyl,piperidinyl, imidazolyl, imidazolidinyl, or morpholinyl, which isunsubstituted or substituted one or more times by alkyl having 1 to 8 Catoms, alkoxy having 1 to 8 C atoms; or a pharmaceutically acceptablesalt thereof, wherein A is attached to the remainder of the compound viaits 3 position.
 59. A method for treating a patient suffering frommemory impairment comprising administering to the patient a compoundaccording to Formula I or Formula II:

wherein A is

X is O or S; R′ is H; R¹ is OH, CN, nitro, NH₂, alkyl having 1 to 4carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, alkenylhaving 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, whereinthe alkyl, fluorinated alkyl, alkenyl, or alkynyl groups are in eachunsubstituted or substituted by Ar or Het, alkoxy having 1 to 4 carbonatoms, cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4to 7 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms,fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxyhaving 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylaminowherein each alkyl group independently has 1 to 4 carbon atoms, Het, orOAr; R² is H, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms; Ar isphenyl which is unsubstituted or substituted one or more times by alkylhaving 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, halogen,dialkylamino wherein the alkyl portions each have 1 to 8 C atoms, amino,cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 C atoms,halogenated alkoxy having 1 to 8 C atoms, hydroxyalkyl having 1 to 8 Catoms, hydroxyalkoxy having 2 to 8 C atoms, alkenyloxy having 3 to 8 Catoms, alkylthio having 1 to 8 C atoms, alkylsulphinyl having 1 to 8 Catoms, alkylsulphonyl having 1 to 8 C atoms, monoalkylamino having 1 to8 C atoms, cycloalkylamino wherein the cycloalkyl group has 3 to 7 Catoms and is optionally substituted, aryloxy wherein the aryl portioncontains 6 to 10 carbon atoms and is optionally substituted, arylthiowherein the aryl portion contains 6 to 10 carbon atoms and is optionallysubstituted, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 Catoms and is optionally substituted, sulfo, sulfonylamino, acylamido,acyloxy or combinations thereof; Het is dihydropyranyl,tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, oxazolyl, pyrrolidinyl,piperidinyl, imidazolyl, imidazolidinyl, or morpholinyl, which isunsubstituted or substituted one or more times by alkyl having 1 to 8 Catoms, alkoxy having 1 to 8 C atoms; or a pharmaceutically acceptablesalt thereof, wherein A is attached to the remainder of the compound viaits 3 position.
 60. A method according to claim 59, wherein said memoryimpairment is due to decreased nicotinic acetylcholine receptoractivity.
 61. (canceled)
 62. (canceled)
 63. (canceled)
 64. (canceled)65. (canceled)
 66. (canceled)
 67. A method of treating a patientsuffering from an inflammatory disease comprising administering to thepatient an effective amount of a compound according to Formula I orFormula II:

wherein A is

X is O or S; R′ is H; R¹ is OH, CN, nitro, NH₂, alkyl having 1 to 4carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, alkenylhaving 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, whereinthe alkyl, fluorinated alkyl, alkenyl, or alkynyl groups are in eachunsubstituted or substituted by Ar or Het, alkoxy having 1 to 4 carbonatoms, cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4to 7 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms,fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxyhaving 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylaminowherein each alkyl group independently has 1 to 4 carbon atoms, Het, orOAr; R² is H, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms; Ar isphenyl which is unsubstituted or substituted one or more times by alkylhaving 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, halogen,dialkylamino wherein the alkyl portions each have 1 to 8 C atoms, amino,cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 C atoms,halogenated alkoxy having 1 to 8 C atoms, hydroxyalkyl having 1 to 8 Catoms, hydroxyalkoxy having 2 to 8 C atoms, alkenyloxy having 3 to 8 Catoms, alkylthio having 1 to 8 C atoms, alkylsulphinyl having 1 to 8 Catoms, alkylsulphonyl having 1 to 8 C atoms, monoalkylamino having 1 to8 C atoms, cycloalkylamino wherein the cycloalkyl group has 3 to 7 Catoms and is optionally substituted, aryloxy wherein the aryl portioncontains 6 to 10 carbon atoms and is optionally substituted, arylthiowherein the aryl portion contains 6 to 10 carbon atoms and is optionallysubstituted, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 Catoms and is optionally substituted, sulfo, sulfonylamino, acylamido,acyloxy or combinations thereof; Het is dihydropyranyl,tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, oxazolyl, pyrrolidinyl,piperidinyl, imidazolyl, imidazolidinyl, or morpholinyl, which isunsubstituted or substituted one or more times by alkyl having 1 to 8 Catoms, alkoxy having 1 to 8 C atoms; or a pharmaceutically acceptablesalt thereof, wherein A is attached to the remainder of the compound viaits 3 position.
 68. A method according to claim 67, wherein saidinflammatory disease is rheumatoid arthritis, diabetes or sepsis.
 69. Amethod according to claim 48, wherein said patient is a human.
 70. Themethod according to claim 48, wherein R′ is H or CH₃.
 71. The methodaccording to claim 48, wherein R¹ is alkynyl having 2 to 6 carbon atoms,fluorinated hydroxyalkyl having 1 to 4 carbon atoms, or Ar-alkynyl. 72.The method according to claim 48, wherein said compound is of formula I.73. The method according to claim 72, wherein R¹ is NH₂, CF₃, OCH₃,OC₂H₅, OCF₃, dihydropyranyl, thiazolyl, oxazolyl, pyrrolidinyl,piperidinyl, or morpholinyl.
 74. The method according to claim 48,wherein X is O.
 75. The method according to claim 48, wherein saidcompound is selected from:6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide,N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-phenoxy-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-piperidin-1-yl-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-pyrrolidin-1-yl-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(pent-1-yn-1-yl)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(phenylethynyl)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-morpholin-4-yl-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-piperidin-1-yl-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-pyrrolidin-1-yl-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-nitro-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(morpholin-4-yl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(prop-1-yn-1-yl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethyl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-nitro-1H-indazole-3-carboxamide,and pharmaceutically acceptable salts thereof.
 76. The method accordingto claim 75, wherein said compound is selected from:N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide,N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-phenoxy-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-piperidin-1-yl-1H-indazole-3-carboxamide,and pharmaceutically acceptable salts thereof.
 77. The method accordingto claim 75, wherein said compound is selected from:N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-pyrrolidin-1-yl-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-nitro-1H-indazole-3-carboxamide,and pharmaceutically acceptable salts thereof.
 78. The method accordingto claim 75, wherein said compound is selected from:6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(pent-1-yn-1-yl)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(phenylethynyl)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide,and pharmaceutically acceptable salts thereof.
 79. The method accordingto claim 75, wherein said compound is selected from:N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-morpholin-4-yl-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-piperidin-1-yl-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-pyrrolidin-1-yl-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(morpholin-4-yl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(prop-1-yn-1-yl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethyl)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-nitro-1H-indazole-3-carboxamide,and pharmaceutically acceptable salts thereof.
 80. The method accordingto claim 75, wherein said compound is in the form of a hydrochloride, ahydroformate or a hydrotrifluoroacetate salt.
 81. The method accordingto claim 80, wherein said compound is selected from:N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamidehydroformate,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamidehydroformate,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamidehydrochloride,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamidehydroformate,N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1H-indazole-3-carboxamidehydroformate,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamidehydroformate,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-phenoxy-1H-indazole-3-carboxamidehydroformate, andN-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-piperidin-1-yl-1H-indazole-3-carboxamidehydroformate.
 82. The method according to claim 80, wherein saidcompound is selected from:N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamidehydrochloride,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamidehydroformate,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxamidehydroformate,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamidehydroformate,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyclopentyl-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamidehydroformate, andN-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamidehydroformate.
 83. The method according to claim 80, wherein saidcompound is selected from:N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydrochloride,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-carboxamidehydroformate,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamidehydroformate,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(pent-1-yn-1-yl)-1H-indazole-3-carboxamidehydroformate,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(phenylethynyl)-1H-indazole-3-carboxamidehydroformate,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamidehydroformate,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamidehydroformate,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamidehydroformate, andN-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamidehydrochloride.
 84. The method according to claim 80, wherein saidcompound is selected from:N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-piperidin-1-yl-1H-indazole-3-carboxamidehydrotrifluoroacetate,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydrochloride,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamidehydroformate,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-carboxamidehydroformate,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamidehydroformate,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(prop-1-yn-1-yl)-1H-indazole-3-carboxamidehydroformate,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamidehydroformate, andN-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamidehydroformate.
 85. The method according to claim 75, wherein saidcompound isN-[1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide,N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide,N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide,or a pharmaceutically acceptable salt thereof.
 86. The method accordingto claim 85, wherein said compound isN-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide,or a pharmaceutically acceptable salt thereof.
 87. The method accordingto claim 86, wherein said compound isN-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamidehydrochloride.